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Head and neck cancers are largely caused by smoking, alcohol and HPV virus (oral sex).Possible is there a (small) familial factor in this large (altough) retrospective trial, so not conclusive on this familial effect.Family history of cancer, personal history of medical conditions and risk of oral cavity cancer in France: the ICARE studyA large study in France confirms thisConclusion:To our knowledge, the ICARE study is the first population-based case–control study in France and one of the largest in the world which investigates the role of risk factors other than tobacco and alcohol consumption in the occurrence of oral cavity cancer. Strengths of this study include large sample size allowing us to perform analyses by subsite, and detailed data about family history of cancer and personal medical history.BackgroundThe aim of this study was to evaluate the role of family history of cancer and personal history of other medical conditions in the aetiology of the oral cavity cancer in FranceMethodsWe used data from 689 cases of cavity squamous cell carcinoma and 3481 controls included in a population-based case–control study, the ICARE study. Odds-ratios (ORs) associated with family history of cancer and personal medical conditions and their 95% confidence intervals (95% CI) were estimated by unconditional logistic regression and were adjusted for age, gender, area of residence, education, body mass index, tobacco smoking and alcohol drinking.ResultsPersonal history of oral candidiasis was related to a significantly increased risk of oral cavity cancer (OR 5.0, 95% CI 2.1-12.1). History of head and neck cancers among the first-degree relatives was associated with an OR of 1.9 (95% CI 1.2-2.8). The risk increased with the number of first-degree relatives with head and neck cancer.ConclusionA family history of head and neck cancer is a marker of an increased risk of oral cavity cancer and should be taken into account to target prevention efforts and screening. Further studies are needed to clarify the association between oral cavity cancer and personal history of candidiasis.Peer Review reportsBackgroundOral cavity cancer (International Classification of Diseases 10th revision (ICD-10) codes C00-C08 [1]) is an important public health burden with an annual worldwide incidence estimated at approximately 263,000 cases, and mortality at 127,000 [2]. Among developed countries, France has the highest age-standardized incidence rate for males (7.6/100,000) and one of the highest for females (1.5/100,000) [3]. As is the case for the other sites of upper aerodigestive tract (UADT), tobacco and alcohol consumption are the main risk factors for oral cavity cancer [4, 5].Besides the role of human papilloma viruses (HPV) 16 and 18 in the aetiology of UADT cancers, few other conditions such as herpetic infection [6–11], candidiasis [6, 10, 11], warts [6, 9–11], and gastro-oesophageal reflux [7] have been investigated. The results of the epidemiological studies on the role of these medical conditions in the occurrence of UADT cancers are contradictory and the underlying mechanisms are not complete elucidated.Other risk factors, such as genetic polymorphism in genes involved in the metabolism of tobacco and alcohol carcinogens and DNA repair seems to play a role in the development of UADT cancers [12–19]. Few epidemiological studies considered the risk of UADT cancers in relatives of subjects with cancer history [20–26]. Familial clustering of UADT cancers may indicate that genetic factors play a role in the process of carcinogenesis, but may also reflect a tendency of relatives to have similar behaviour towards tobacco and alcohol. Limited data are available on the combined effect of family history, and tobacco and alcohol consumption [20, 23, 26]. The literature is contrasted about whether the cancer risk varies according to UADT subsite, gender, type of affected relative (parents, siblings), and their cancer site.The present work aimed to investigate the role of family history of cancer and personal medical history in the aetiology of oral cavity cancer in France using data from a large case–control study, the ICARE study.MethodsICARE studyThe ICARE study (Investigation of occupational and environmental CAuses of REspiratory cancers) is a multicentre population-based case–control study on lung and upper aerodigestive tract cancers carried out from 2001 to 2007 in 10 French administrative areas (“départements”) covered by a general cancer registry. This study was set up to explore the role of lifestyle, environmental and occupational risk factors in lung and UADT cancers. The study design has been described in details elsewhere [27].Briefly, all newly diagnosed primary oral cavity, pharynx, larynx, sinusal cavities, trachea and lung cancers were selected. Only histologically confirmed cases aged 75 or younger at interview, identified between 2001 and 2007, and residing in one of the 10 départements, were eligible. Clinical and anatomo-pathology reports were reviewed to determine topography and histological type of the tumours according to the International Classification of Diseases for Oncology [28]. All histological types were included.Controls were selected from the general population by random digit dialling [29]. The controls were frequency-matched to the cases by age, gender and area of residence (“département”). Additional stratification ensured that controls were representative of the population of the “département” in terms of socio-economic status based on the last job held.Present analysisThe present analysis included all ICARE controls and only the cases with oral cavity cancer (ICD-10 codes C01-C06).Among the 1316 oral cavity cancer cases identified as eligible, 196 could not be reached, 81 were deceased and 71 were too sick to be interviewed. Of the 968 cases who were contacted, 176 refused to participate and 792 (81.8%) answered the questionnaire. We focused only on the cases with squamous cell carcinoma (772 subjects, 97.5% of all cases with oral cavity cancer).Of 4673 eligible controls, 4411 were contacted, and 3555 (80.6%) agreed to participate.Data collectionTrained interviewers administered a detailed standardised questionnaire during face-to-face interviews. If the subject was too sick to be interviewed, a shortened version of the questionnaire was used to interview him or a next-of-kin. Among the 772 subjects with squamous cell carcinoma of the oral cavity, 689 (89.2%) filled a complete questionnaire and 83 (10.8%) a shortened questionnaire. Among controls, 3481 (97.9%) filled a complete questionnaire and 74 a shortened questionnaire (2.1%). As the shortened version of the questionnaire did not contain information about family history of cancer and medical conditions, the present analysis was based on 689 cases with squamous cell carcinoma and 3481 controls, all with a complete questionnaire.The complete questionnaire consisted of the following items: socio-demographic characteristics (age, gender, birth country, education level, marital status), residential history, personal medical history, family history of cancer, detailed tobacco and alcohol consumption (quantity, duration, type of product, age at starting, time since cessation), non-alcoholic beverage consumption (coffee, tea), anthropometric variables (height, weight at interview, two years before and at age 30), detailed lifelong job history and occupational exposures.To ascertain personal medical history, study participants were asked if, throughout their lives, they had ever had (“yes, no, or don’t know”) any of the following diseases: tuberculosis, chronic bronchitis, asthma, recurrent rhinitis, nasal polyps, recurrent nose bleeds, recurrent sinusitis, gastro-oesophageal reflux (heartburn or regurgitation), herpes, candidiasis, and warts. If the answer was “yes”, the subjects were asked to specify the age at first occurrence, the treatment and if the diagnosis was made by a doctor. Subjects reporting having ever had herpes, candidiasis or warts were asked to specify the location: lip and genitals for herpes, oral cavity and genitals for candidiasis, and hands, feet and head and neck for warts.To ascertain the family history of cancer, subjects were first asked to give the year of birth of their biological mother and father, and of their full brothers or sisters (“brother or sister having the same mother and the same father than you”). Then, they were asked for each of these relatives if she/he had ever had a cancer (“yes, no or don’t know”). If the answer was “yes”, the subjects were asked to specify the age at cancer diagnosis and if possible the type of cancer. No verification of the cancer diagnosis in the relatives was performed.Statistical analysisWe used unconditional logistic regression models to calculate odds ratios (OR) and their 95% confidence intervals (95% CI). All p-values were derived from two-sided statistical tests.All logistic regression models controlled for age (≤ 50, 51–59, 60–69, ≥ 70 years), gender, area of residence, education level (primary or less, vocational secondary, general secondary and university), BMI two years before the interview (categorical, according to the classification of the World Health Organization [30]: < 18.5, 18.5-24.9, 25.0-29.9, ≥ 30 kg/m2). Previous analyses of our data showed that the variables that best characterize the association between tobacco and alcohol consumption and oral cancer risk were smoking status, smoking duration, daily quantity of tobacco smoked and daily quantity of alcohol drinking [31]. To control for smoking, we used smoking status (never, current, former), average daily quantity of tobacco smoked (1–19, 20–39, ≥ 40 grams), and duration of smoking (1–30, 31–40, > 40 years) [32]. Average daily quantity of alcohol drinking in quartiles (never, < 0.6, 0.6-2.0, 2.1-4.5, > 4.5 standard glasses) was included in the models to adjust for alcohol drinking. The quantity of pure alcohol contained in a standard glass (15 cl of wine, 30 cl of beer, 5 cl of spirits, 10 cl of aperitif, and 30 cl of cider) is the same for each type of alcoholic beverage.We analysed the risk of oral cavity cancer related to the personal medical history using two variables: all medical conditions self-reported by the subjects and medical conditions reportedly diagnosed by a doctor. The date of interview was used as the date of reference for both cases and controls. This date was close to the date of diagnosis of the cases since cases were interviewed on average within three months of diagnosis.The family history of cancer was evaluated separately for mothers, fathers, brothers and sisters, and then among all first-degree relatives taken together. We analysed the risk of oral cavity cancer related to the cancer site among relatives: all sites together, head and neck (including oral cavity, pharynx, larynx, nasal cavity and sinuses) and non-head and neck cancers. Because a high number of cancers in family members were reported non-specifically as “cancer of the head and neck”, we chose to group the locations of head and neck cancers to reduce potential inaccurate reporting of cancer subsites. We nevertheless performed some analyses for family history of specific head and neck cancer sites among all first-degree relatives.We also conducted analyses stratified by tobacco and alcohol consumption. We also performed the same analyses using a more restricted definition of the oral cavity excluding base of tongue (C01), lingual tonsils (C02.4), soft palate (C05.1) and uvula (C05.2), since these subsites are often included in the oropharynx. In addition, seven subsites (base of the tongue, mobile tongue, floor of the mouth, gums, soft palate, hard palate, and other parts of the oral cavity) were compared for family history of cancer and personal history of other medical conditions using unconditional polytomous logistic regression.Statistical analyses were conducted using STATA software version 10.0 (StataCorp, Texas, USA).ResultsAmong the 689 cases, the most common tumour location was floor of the mouth (188 cases, 27.3%), followed by mobile tongue (162 cases, 23.5%) and base of the tongue (130 cases, 18.9%). Less frequent tumour locations were: other parts of the oral cavity (81 cases, 11.7%), soft palate (74 cases, 10.7%), gums (37 cases, 5.4%), and hard palate (17 cases, 2.5%). The analysis using the restricted definition of oral cavity involved 485 cases.The main characteristics of cases and controls are presented in Table 1.Table 1 Main characteristics of cases and controlsFull size tableMen represented more than two-thirds of subjects in both cases and controls. Cases were younger (mean age around 57 years) than controls (mean age around 59 years) (p < 0.001).Compared with controls, cases had a lower education level (p < 0.001), a higher consumption of tobacco (p < 0.001) and alcohol (p < 0.001), and a lower BMI two years before the interview (p < 0.001).Personal medical conditionsStatistical analysis showed significant positive associations between the risk of oral cavity cancer (C01-C06) and chronic bronchitis (OR 1.7, 95% CI 1.2-2.4) (Table 2). Histories of tuberculosis and candidiasis overall were associated with an increased risk of oral cavity cancer (ORs 1.6), but the results did not reach statistical significance. Among candidiasis locations, oral candidiasis was associated with an increased risk of oral cavity cancer (OR 5.0, 95% CI 2.1-12.1). Significant inverse relations were observed between the risk of oral cavity cancer and recurrent rhinitis (OR 0.6, 95% CI 0.4-0.9), nasal polyps (OR 0.3, 95% CI 0.1-0.9), and gastro-oesophageal reflux (OR 0.5, 95% CI 0.4-0.7). Herpetic lesions were not related to the risk of oral cavity cancer, regardless of the location of the herpes. The risks associated with a history of skin warts were reduced, but the results did not reach statistical significanceTable 2 Risks of oral cavity cancer associated with personal medical conditionsFull size tableBecause high prevalence of oropharyngeal candidiasis has been described in subjects with head and neck cancer undergoing radio/chemotherapy [33, 34], we also conducted analysis after excluding subjects declaring candidiasis at the time of interview or at the time of diagnosis of another cancer; the association between oral cavity cancer risk and oral candidiasis remained practically unchanged (OR 6.0, 95% CI 2.2-16.4). Oral candidiasis may also constitute an early manifestation of the cancerous disease. When we excluded all subjects reporting a history of oral candidiasis near the current cancer (up to two years before the cancer diagnosis), the association between oral cavity cancer and oral candidiasis remained significant (OR 3.7, CI 95% 1.3-10.1).We calculated the ORs for oral candidiasis in strata of tobacco and alcohol consumption. The OR was slightly higher in ever smokers (OR 5.6, 95% CI 2.0-15.2) than in never smokers (OR 4.3, 95% CI 0.5-41.7), but the interaction between tobacco smoking and oral candidiasis was not significant (p-value for interaction = 0.14). Oral candidiasis was associated with an elevated risk of oral cavity cancer in drinkers of more than 2 glasses/day (OR 3.9, 95% CI 1.0-14.8) but not in drinkers of 2 glasses/day or less (OR 1.1, 95% CI 0.2-23.8), although the ORs were not statistically different (p-value for interaction = 0.50).When the analysis was restricted to medical conditions that the subjects reported as diagnosed by a doctor, similar results were observed, except for the association between bronchitis and oral cavity cancer which became weaker and non-significant (OR 1.2, 95% CI 0.9-1.6) (data not shown).Family history of cancerThe associations between family history of cancer and risk of oral cavity cancer are presented in Table 3.Table 3 Risks of oral cavity cancer associated with family history of cancer among first-degree relativesFull size tableHistory of cancer in general, and of head and neck cancer in particular, among fathers, were associated with a slightly elevated risk of oral cavity cancer, but the results were not statistically significant (OR 1.3, 95% CI 0.9-1.6, and 1.5, 95% CI 0.9-2.4, respectively).History of head and neck cancer among mothers was significantly associated with an elevated risk of oral cavity cancer (OR 5.2, 95% CI 1.2-23.9). This OR was higher than that observed for fathers. When cancer history among siblings was analysed, after adjustment for the number of sisters and brothers, we observed a significant association between the risk of oral cavity cancer and history of cancer of any type (OR 1.4, 95% CI 1.1-1.9). History of head and neck cancer among siblings was associated with an increased risk of oral cavity cancer (OR 2.3, 95% CI 1.2-4.2). Analysis by type of sibling showed a significantly increased risk only among subjects having brothers with a history of head and neck cancer (OR 2.6, 95% CI 1.2-5.8); history of head and neck cancer among sisters was not significantly associated with an increased risk of oral cavity cancer (OR 1.7, 95% CI 0.6-4.2).When we analysed the relationship between cancer history among all first-degree relatives and oral cavity cancer risk, we observed significant association for history of head and neck cancer (OR 1.9, 95% CI 1.2-2.8). A family history of any type of cancer slightly increased the risk of oral cavity cancer, but the results were not statistically significant (OR 1.2, 95% CI 0.9-1.5). The risk associated with first-degree relatives’ history of cancer (any type and head and neck) increased with the number of affected relatives.Analysis by type of head and neck cancer in first-degree relatives showed significantly increased risks of oral cavity cancer in subjects with family history of oral cavity cancer (OR 3.5, 95% CI 1.1-11.2) and of “head and neck cancer” (not specified) (OR 1.8, 95% CI 1.1-2.9). A family history of pharyngeal, laryngeal, and sinonasal cancer was associated with non-significantly elevated risks of oral cavity cancer (OR 4.6, 95% CI 0.5-44.8 for history of pharyngeal cancer; 1.6, 95% CI 0.6-4.4 for history of laryngeal cancer; and 1.7, 95% CI 0.3-8.8 for history of sinonasal cancer). However, few subjects reported a specific location of head and neck cancer in first degree relatives (26 oral cavity, 5 pharynx, 35 larynx, and 11 nasal cavity/sinuses cancer).Analysis stratified by gender of first-degree relatives showed that history of head and neck cancer among female relatives (mothers and sisters) was not significantly associated with the risk of oral cavity cancer (OR 2.3, 95% CI 0.9-5.4), although the result was borderline significant. Conversely, history of head and neck cancer in male relatives (fathers and brothers) was significantly associated with the risk of oral cavity cancer (OR 1.9, 95% CI 1.2-3.3). However, these ORs did not differ significantly (p-value of test of comparison of ORs = 0.91).We found a stronger association between the risk of oral cavity cancer and family history of head and neck cancer in subjects aged 45 or more (OR 2.3, 95% CI 1.5-3.4) compared to subjects aged less than 45 (OR 1.3, 95% CI 0.3-6.7), although the ORs were not statistically different (p-value for interaction = 0.46).Analysis by cancer site among first-degree relatives (Table 4) showed elevated ORs among subjects having a family history of lung, oesophagus, cervix and corpus uteri, brain and nervous system cancer, but the results were not statistically significant (OR 1.4, 95% CI 0.9-1.9; 1.5, 95% CI 0.7-3.3; 1.7, 95% CI 0.9-3.1; 2.0, 95% CI 0.9-4.8 respectively).Table 4 Odds ratios for oral cavity cancer risk related to family history of selected cancers in first-degree relativesFull size tableWhen we stratified by tobacco smoking and/or alcohol drinking (Table 5), significantly increased risks of oral cavity cancer related to family history of any type of cancer were observed only in smokers and/or moderate to heavy drinkers. Significantly elevated risks of oral cavity cancer associated with family history of head and neck cancer were seen for both never and ever smokers and for light and moderate to heavy drinkers. However, the increase in risk was small and not significant for never smokers who were also light drinkers.Table 5 Risks of oral cavity cancer related to family history of cancer in first-degree relatives stratified by tobacco smoking and alcohol drinkingFull size tableAnalyses restricted to intraoral cavityWhen the analyses were limited to intraoral cavity (C02.0-C02.3, C02.8, C02.9, C03, C04, C05.0, C05.8, C05.9, C06), the results were similar to that observed for oral cavity globally (C01-C06). Thus, family history of UADT cancer among first-degree relatives was associated with an OR of 1.7 (95% CI 1.1-2.7), personal history of oral candidiasis with an OR of 4.9 (95% CI 1.8-13.3), gastro-oesophageal reflux with an OR of 0.6 (95% CI 0.4-0.8), recurrent rhinitis with an OR of 0.6 (95% CI 0.4-0.9), and nasal polyps with an OR of 0.3 (95% CI 0.1-0.9).Analyses by subsiteWe assessed the risk of oral cavity cancer by anatomical site of the oral cavity (base of tongue, mobile tongue, gum, floor of mouth, hard and soft palate, and other parts of oral cavity) for personal medical conditions and for family history of cancer using a polytomous regression. We did not find any difference between subsites for any variable of interest (tests of comparison of odds ratios non-significant) (data not shown).DiscussionTo our knowledge, the ICARE study is the first population-based case–control study in France and one of the largest in the world which investigates the role of risk factors other than tobacco and alcohol consumption in the occurrence of oral cavity cancer. Strengths of this study include large sample size allowing us to perform analyses by subsite, and detailed data about family history of cancer and personal medical history.The ICARE study was conducted in collaboration with the cancer registries, allowing us to recruit cancer cases in all healthcare establishments in the selected areas. The control group was population-based and common for both pathologies (lung and UADT cancers), which explains the significantly different distribution of age and area of residence between oral cavity cancer cases and controls. However, the large number of subjects in each category allowed for satisfactory adjustment for these variables.The results of the epidemiological studies are contrasted concerning the role of candidiasis in the occurrence of oral cavity cancer, Thus, history of oral candidiasis was associated with an increased risk of oral cavity and oropharyngeal cancer in one study [11], with a reduced risk of oral cavity cancer in another study [7], whereas other authors found no association [6]. Our results have shown that personal history of oral candidiasis was associated with an elevated risk of oral cavity cancer. The increase in cancer risk with oral candidiasis may be explained by the production of endogenous nitrosamines by Candida albicans[35]. These nitrosamines act on the normal epithelium leading to oral dysplasia and further development of oral carcinoma. Nevertheless, some authors suggested that Candida albicans have only an indirect role and that the possibility of their involvement exist in conjunction with other etiological factors such as tobacco smoking [36]. In our study, the risk of oral cavity cancer associated with history of candidiasis was slightly higher in smokers than in never smokers, but the ORs were not significantly different. Other studies showed that Candida albicans may metabolize ethanol into its carcinogenic metabolite, acetaldehyde and, accordingly, candidiasis may be associated with elevated acetaldehyde levels in the oral cavity [37, 38]. Consistent with this mechanism, we found a significantly elevated risk of oral cavity cancer associated with history of candidiasis in moderate to heavy drinkers but not in light drinkers. However, the interaction of oral candidiasis with alcohol drinking was not statistically significant. Also, chronic infections, specifically chronic hyperplastic candidiasis, may trigger cell proliferation, inhibit apoptosis, interfere with cellular signalling mechanisms and up-regulate tumour promoters [39, 40]. In our study only 14 cases and 80 controls reported prior candidiasis and the results should be confirmed by other studies, especially with medical conditions validated by a doctor.In agreement with previous studies [7, 8, 11], we did not find a significant association between the risk of oral cavity cancer and history of herpetic infection. Conversely, only one case–control study [10] found an increased risk of oral cavity and oropharynx cancer associated with this infection and two case–control studies [6, 9] found a decreased risk.Cutaneous warts are caused by different types of HPV, notably 2, 4, 7 and 57, whereas genital warts are caused mostly by HPV types 6 and 11 [41]. Three studies [6, 8, 11], like ours, did not find any association between history of warts (any location) and the risk of oral cavity cancer, whereas one study found a reduced risk of UADT cancer associated with feet, genital and head and neck warts [7].We found an inverse association between the oral cavity cancer risk and history of rhinitis and nasal polyps. These pathologies often have an allergic origin, and several studies found a decreased risk of head and neck cancer associated with a history of allergies [42–45]. The inverse association between allergies and cancer may be explained by an overactive immune function in allergic subjects that effectively detects and eradicates malignant cells, toxins or pathogens from the body [46, 47]. However, we did not find any association with the history of asthma, another allergies-related condition.We found also an inverse association between oral cavity cancer risk and history of gastro-oesophageal reflux but we cannot point to any specific mechanism. The possibility that this result is due to the chance may not be ruled out. Unlike our results, a recent case–control study [7] did not find any association between oral cavity cancer risk and gastro-oesophageal reflux.After controlling for main confounding factors, we observed a higher risk of oral cavity cancer among subjects having first-degree relatives with head and neck cancer history, compared to subjects without such a family history. The risk increased with the number of affected relatives. On the other hand we did not find a significant relationship between the risk of oral cavity cancer and family history of non-head and neck cancers. Several studies [20, 22, 23, 26] reported similar results.Early age of onset may be a feature of hereditary forms of cancer. Higher family risks for many cancers were found when the cancer subjects were diagnosed at an early age [48, 49]. Concerning the association between the risk of oral cancer and family history of head and neck cancer, no clear pattern emerges from epidemiological studies: some of them found a stronger association in younger subjects compared to older subjects [20, 21, 23], others found a contrary result [22, 26], but the differences in risk with age of onset were never significant. Similarly, in our study the interaction of family history of head and neck cancer with age was not significant, although the OR was somewhat higher in older subjects.Familial clustering of cancer cases could be explained by genetic polymorphism in genes involved in the metabolism of tobacco and alcohol carcinogens and DNA repair [12–19], but may also reflect a tendency of relatives to have similar behaviour concerning alcohol and tobacco.In our study, associations between oral cavity cancer risk and family history of cancer were observed among smokers and/or drinkers of >2 glasses/day only. Conversely, an increased risk of oral cavity cancer associated with a family history of head and neck cancer was also observed in non-smokers and light drinkers, but the risk increased with the exposure. Our results are similar to those of other studies on oral/pharyngeal or head and neck cancer [20, 23, 26].The differential ability of subjects to metabolize carcinogens when exposure to tobacco and/or alcohol occurs may explain the higher risk of oral cavity cancer observed in our study among smokers and drinkers having a family history of UADT cancer. Nevertheless, we did not observe an increased risk of oral cavity cancer in subjects having a family history of other cancers related to smoking and/or alcohol drinking (e.g. lung, oesophagus, liver, pancreas), suggesting that other genetic factors might explain these findings.When the analyses were limited to intraoral cavity (C02.0-C02.3, C02.8, C02.9, C03, C04, C05.0, C05.8, C05.9, C06), excluding the sites usually attached to oropharynx (C01, C02.4, C05.1, C05.2), the results were similar to that observed for oral cavity C01-C06. We did not find any difference between subsites base of the tongue, mobile tongue, gums, floor of the mouth, soft palate, hard palate, and other parts of the mouth for any variable of interest.Some limitations of our study can be discussed. The subjects self-reported their own medical history and family history of cancer. Thereby, recall bias could not be ruled out and it is possible that the cases had a higher motivation to recall their personal and family medical history than the controls. Nevertheless, two studies have shown that subjects in case–control studies are able to report accurately family history of common types of cancer among first-degree relatives, with little observable recall bias [50, 51]. In addition, family history of cancer sites other than head and neck was not associated with an increased risk of oral cavity cancer in this study, suggesting that no major recall bias concerning cancer in general has affected our results.With regards to oral candidiasis, a possible explanation would be that cases with oral cancer are more prone to recall previous oral lesions than controls. However, no association was found with labial herpes, another oral condition, suggesting that differential recall between cases and controls is unlikely to explain our results. Moreover, when we limited the medical conditions to those reportedly diagnosed by a doctor, the results were similar. Medical treatments were also collected and those reported for candidiasis were consistent with this pathology. So, we think that misclassification of candidiasis is unlikely to explain our results.Information about other known risk factors for oral cavity cancer such as diet, human papilloma virus (HPV) or dental health was not collected, and residual confounding cannot be excluded. Nevertheless, no association between diet, HPV infection or dental health and family history of cancer has ever been shown in the literature. Also, the possibility of residual confounding for the main risk factors may not be ruled out.We have no way to assess whether cases included in our study differed according to past medical conditions and family history of cancer from cases that could not be included. Nevertheless, the distribution of included cases by age, gender and cancer subsite was very similar to that of all oral cancer cases diagnosed in France [52], suggesting that no major selection bias occurred. We excluded from analysis all subjects with shortened questionnaires because information on medical conditions and family history of cancer was not available. However, these subjects were comparable in age, gender, and tobacco and alcohol consumption to subjects with complete questionnaires.ConclusionThis study showed that family history of head and neck cancer is related to an increased risk of oral cavity cancer, and suggested an association with personal history of oral candidiasis. From a public health point of view, these factors should be taken into account to target prevention efforts and screening.References1.World Health Organization: International Classification of Diseases 10th Revision. 2007, Geneva: World Health OrganizationGoogle Scholar2.Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010, 127: 2893-2917. 10.1002/ijc.25516.CASArticlePubMedGoogle Scholar3.de Camargo CM, Voti L, Guerra-Yi M, Chapuis F, Mazuir M, Curado MP: Oral cavity cancer in developed and in developing countries: population-based incidence. Head Neck. 2010, 32: 357-367.Google Scholar4.International Agency for Research on Cancer: IARC Monographs on Evaluation of Carcinogenic Risk to Humans. Tobacco smoke and involuntary smoking. Volume 83. 2004, Lyon: IARC PressGoogle Scholar5.International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Alcohol consumption and ethyl carbamate. Volume 96. 2005, Lyon: IARC PressGoogle Scholar6.Garrote LF, Herrero R, Reyes RM, Vaccarella S, Anta JL, Ferbeye L, Munoz N, Franceschi S: Risk factors for cancer of the oral cavity and oro-pharynx in Cuba. Br J Cancer. 2001, 85: 46-54. 10.1054/bjoc.2000.1825.CASArticlePubMedPubMed CentralGoogle Scholar7.Macfarlane TV, Macfarlane GJ, Thakker NS, Benhamou S, Bouchardy C, Ahrens W, Pohlabeln H, Lagiou P, Lagiou A, Castellsague X, Agudo A, Slamova A, Plzak J, Merletti F, Richiardi L, Talamini R, Barzan L, Kjaerheim K, Canova C, Simonato L, Conway DI, McKinney PA, Thomson P, Sloan P, Znaor A, Healy CM, McCartan BE, Marron M, Brennan P: Role of medical history and medication use in the aetiology of upper aerodigestive tract cancers in Europe: the ARCAGE study. Ann Oncol. 2012, 23: 1053-1060. 10.1093/annonc/mdr335.CASArticlePubMedGoogle Scholar8.Maden C, Beckmann AM, Thomas DB, McKnight B, Sherman KJ, Ashley RL, Corey L, Daling JR: Human papillomaviruses, herpes simplex viruses, and the risk of oral cancer in men. Am J Epidemiol. 1992, 135: 1093-1102.CASPubMedGoogle Scholar9.Rosenquist K, Wennerberg J, Schildt EB, Bladstrom A, Goran HB, Andersson G: Oral status, oral infections and some lifestyle factors as risk factors for oral and oropharyngeal squamous cell carcinoma. A population-based case–control study in southern Sweden. Acta Otolaryngol. 2005, 125: 1327-1336. 10.1080/00016480510012273.ArticlePubMedGoogle Scholar10.Schildt EB, Eriksson M, Hardell L, Magnuson A: Oral infections and dental factors in relation to oral cancer: a Swedish case–control study. Eur J Cancer Prev. 1998, 7: 201-206.CASArticlePubMedGoogle Scholar11.Talamini R, Vaccarella S, Barbone F, Tavani A, La VC, Herrero R, Munoz N, Franceschi S: Oral hygiene, dentition, sexual habits and risk of oral cancer. Br J Cancer. 2000, 83: 1238-1242. 10.1054/bjoc.2000.1398.CASArticlePubMedPubMed CentralGoogle Scholar12.Benhamou S, Tuimala J, Bouchardy C, Dayer P, Sarasin A, Hirvonen A: DNA repair gene XRCC2 and XRCC3 polymorphisms and susceptibility to cancers of the upper aerodigestive tract. Int J Cancer. 2004, 112: 901-904. 10.1002/ijc.20474.CASArticlePubMedGoogle Scholar13.Danoy P, Michiels S, Dessen P, Pignat C, Boulet T, Monet M, Bouchardy C, Lathrop M, Sarasin A, Benhamou S: Variants in DNA double-strand break repair and DNA damage-response genes and susceptibility to lung and head and neck cancers. Int J Cancer. 2008, 123: 457-463. 10.1002/ijc.23524.CASArticlePubMedGoogle Scholar14.Hashibe M, Brennan P, Strange RC, Bhisey R, Cascorbi I, Lazarus P, Oude Ophuis MB, Benhamou S, Foulkes WD, Katoh T, Coutelle C, Romkes M, Gaspari L, Taioli E, Boffetta P: Meta- and pooled analyses of GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes and risk of head and neck cancer. Cancer Epidemiol Biomarkers Prev. 2003, 12: 1509-1517.CASPubMedGoogle Scholar15.Lacko M, Oude Ophuis MB, Peters WH, Manni JJ: Genetic polymorphisms of smoking-related carcinogen detoxifying enzymes and head and neck cancer susceptibility. Anticancer Res. 2009, 29: 753-761.PubMedGoogle Scholar16.McKay JD, Truong T, Gaborieau V, Chabrier A, Chuang SC, Byrnes G, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Bucur A, Bencko V, Holcatova I, Janout V, Foretova L, Lagiou P, Trichopoulos D, Benhamou S, Bouchardy C, Ahrens W, Merletti F, Richiardi L, Talamini R, Barzan L, Kjaerheim K, Macfarlane GJ, Macfarlane TV, Simonato L, et al: A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium. PLoS Genet. 2011, 7: e1001333-10.1371/journal.pgen.1001333.CASArticlePubMedPubMed CentralGoogle Scholar17.Michiels S, Danoy P, Dessen P, Bera A, Boulet T, Bouchardy C, Lathrop M, Sarasin A, Benhamou S: Polymorphism discovery in 62 DNA repair genes and haplotype associations with risks for lung and head and neck cancers. Carcinogenesis. 2007, 28: 1731-1739. 10.1093/carcin/bgm111.CASArticlePubMedGoogle Scholar18.Oude Ophuis MB, Roelofs HM, van den Brandt PA, Peters WH, Manni JJ: Polymorphisms of the glutathione S-transferase P1 gene and head and neck cancer susceptibility. Head Neck. 2003, 25: 37-43. 10.1002/hed.10182.ArticlePubMedGoogle Scholar19.Peters ES, McClean MD, Marsit CJ, Luckett B, Kelsey KT: Glutathione S-transferase polymorphisms and the synergy of alcohol and tobacco in oral, pharyngeal, and laryngeal carcinoma. Cancer Epidemiol Biomarkers Prev. 2006, 15: 2196-2202. 10.1158/1055-9965.EPI-06-0503.CASArticlePubMedGoogle Scholar20.Brown LM, Gridley G, Diehl SR, Winn DM, Harty LC, Otero EB, Fraumeni JF, Hayes RB: Family cancer history and susceptibility to oral carcinoma in Puerto Rico. Cancer. 2001, 92: 2102-2108. 10.1002/1097-0142(20011015)92:8<2102::AID-CNCR1551>http://3.0.CO;2-9.CASArticlePubMedGoogle Scholar21.Foulkes WD, Brunet JS, Kowalski LP, Narod SA, Franco EL: Family history of cancer is a risk factor for squamous cell carcinoma of the head and neck in Brazil: a case–control study. Int J Cancer. 1995, 63: 769-773. 10.1002/ijc.2910630603.CASArticlePubMedGoogle Scholar22.Foulkes WD, Brunet JS, Sieh W, Black MJ, Shenouda G, Narod SA: Familial risks of squamous cell carcinoma of the head and neck: retrospective case–control study. BMJ. 1996, 313: 716-721. 10.1136/bmj.313.7059.716.CASArticlePubMedPubMed CentralGoogle Scholar23.Garavello W, Foschi R, Talamini R, La VC, Rossi M, Dal ML, Tavani A, Levi F, Barzan L, Ramazzotti V, Franceschi S, Negri E: Family history and the risk of oral and pharyngeal cancer. Int J Cancer. 2008, 122: 1827-1831.CASArticlePubMedGoogle Scholar24.Goldstein AM, Blot WJ, Greenberg RS, Schoenberg JB, Austin DF, Preston-Martin S, Winn DM, Bernstein L, McLaughlin JK, Fraumeni JF: Familial risk in oral and pharyngeal cancer. Eur J Cancer B Oral Oncol. 1994, 30B: 319-322.CASArticlePubMedGoogle Scholar25.Mork J, Moller B, Glattre E: Familial risk in head and neck squamous cell carcinoma diagnosed before the age of 45: a population-based study. Oral Oncol. 1999, 35: 360-367. 10.1016/S1368-8375(98)00069-4.CASArticlePubMedGoogle Scholar26.Negri E, Boffetta P, Berthiller J, Castellsague X, Curado MP, Dal ML, Daudt AW, Fabianova E, Fernandez L, Wunsch-Filho V, Franceschi S, Hayes RB, Herrero R, Koifman S, Lazarus P, Lence JJ, Levi F, Mates D, Matos E, Menezes A, Muscat J, Eluf-Neto J, Olshan AF, Rudnai P, Shangina O, Sturgis EM, Szeszenia-Dabrowska N, Talamini R, Wei Q, Winn DM, et al: Family history of cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Int J Cancer. 2009, 124: 394-401. 10.1002/ijc.23848.CASArticlePubMedPubMed CentralGoogle Scholar27.Luce D, Stucker I: Icare Study Group: Investigation of occupational and environmental causes of respiratory cancers (ICARE): a multicenter, population-based case–control study in France. BMC Public Health. 2011, 11: 928-10.1186/1471-2458-11-928.ArticlePubMedPubMed CentralGoogle Scholar28.World Health Organization: International Classification of Diseases for Oncology 3rd Edition. 2000, Geneva: World Health OrganizationGoogle Scholar29.Rothman KJ, Greenland S, Lash TL: Study design and conduction. Case–control studies. Modern Epidemiology. Edited by: Rothman KJ, Greenland S, Lash TL. 2008, Philadelphia: Lippincott Williams and Wilkins, 117-119. 3Google Scholar30.World Health Organization. Obesity: Preventing and managing the global epidemic. Report of a WHO Consultation. WHO Technical Report Series 894. 2000, Geneva: World Health OrganizationGoogle Scholar31.Radoi L, Paget-Bailly S, Cyr D, Papadopoulos A, Guida F, Schmaus A, Cenee S, Menvielle G, Carton M, Lapotre-Ledoux B, Delafosse P, Stucker I, Luce D: Tobacco smoking, alcohol drinking and risk of oral cavity cancer by subsite: results of a French population-based case–control study, the ICARE study. Eur J Cancer Prev. 2013, 22: 268-276. 10.1097/CEJ.0b013e3283592cce.CASArticlePubMedGoogle Scholar32.McKnight B, Cook LS, Weiss NS: Logistic regression analysis for more than one characteristic of exposure. Am J Epidemiol. 1999, 149: 984-992. 10.1093/oxfordjournals.aje.a009759.CASArticlePubMedGoogle Scholar33.Manas A, Cerezo L, de la Torre A, Garcia M, Alburquerque H, Ludena B, Ruiz A, Perez A, Escribano A, Manso A, Glaria LA: Epidemiology and prevalence of oropharyngeal candidiasis in Spanish patients with head and neck tumors undergoing radiotherapy treatment alone or in combination with chemotherapy. Clin Transl Oncol. 2012, 14: 740-746. 10.1007/s12094-012-0861-8.CASArticlePubMedGoogle Scholar34.Pinel B, Cassou-Mounat T, Bensadoun RJ: Oropharyngeal candidiasis and radiotherapy. Cancer Radiother. 2012, 16: 222-229. 10.1016/j.canrad.2011.11.004.CASArticlePubMedGoogle Scholar35.Krogh P: The role of yeasts in oral cancer by means of endogenous nitrosation. Acta Odontol Scand. 1990, 48: 85-88. 10.3109/00016359009012738.CASArticlePubMedGoogle Scholar36.Sanjaya PR, Gokul S, Gururaj PB, Raju R: Candida in oral pre-cancer and oral cancer. Med Hypotheses. 2011, 77: 1125-1128. 10.1016/j.mehy.2011.09.018.CASArticlePubMedGoogle Scholar37.Homann N, Tillonen J, Meurman JH, Rintamaki H, Lindqvist C, Rautio M, Jousimies-Somer H, Salaspuro M: Increased salivary acetaldehyde levels in heavy drinkers and smokers: a microbiological approach to oral cavity cancer. Carcinogenesis. 2000, 21: 663-668. 10.1093/carcin/21.4.663.CASArticlePubMedGoogle Scholar38.Hooper SJ, Wilson MJ, Crean SJ: Exploring the link between microorganisms and oral cancer: a systematic review of the literature. Head Neck. 2009, 31: 1228-1239. 10.1002/hed.21140.ArticlePubMedGoogle Scholar39.Meurman JH: Infectious and dietary risk factors of oral cancer. Oral Oncol. 2010, 46: 411-413. 10.1016/j.oraloncology.2010.03.003.ArticlePubMedGoogle Scholar40.Mohd BM, Mohd HH, Rachel HA, David CR, Mary RA: Revisiting the association between candidal infection and carcinoma, particularly oral squamous cell carcinoma. J Oral Microbiol. 2010, 2: 5780-Google Scholar41.International Agency for Research on Cancer: IARC Monographs on Evaluation of Carcinogenic Risk to Humans. Human Papillomaviruses. Volume 90. 2007, Lyon: IARC Press editionGoogle Scholar42.Bosetti C, Talamini R, Franceschi S, Negri E, Giacosa A, La Vecchia C: Allergy and the risk of selected digestive and laryngeal neoplasms. Eur J Cancer Prev. 2004, 13: 173-176. 10.1097/01.cej.0000130016.85687.cf.CASArticlePubMedGoogle Scholar43.Hsiao JR, Ou CY, Lo HI, Huang CC, Lee WT, Huang JS, Chen KC, Wong TY, Tsai ST, Yen CJ, Wu YH, Hsueh WT, Yang MW, Wu SY, Chang JY, Chang KY, Lin CL, Wang FT, Wang YH, Weng YL, Yang HC, Chang JS: Allergies and risk of head and neck cancer: an original study plus meta-analysis. PLoS One. 2013, 8: e55138-10.1371/journal.pone.0055138.CASArticlePubMedPubMed CentralGoogle Scholar44.Michaud DS, Langevin SM, Eliot M, Nelson HH, McClean MD, Christensen BC, Marsit CJ, Kelsey KT: Allergies and risk of head and neck cancer. Cancer Causes Control. 2012, 23: 1317-1322. 10.1007/s10552-012-0009-8.ArticlePubMedPubMed CentralGoogle Scholar45.Vena JE, Bona JR, Byers TE, Middleton E, Swanson MK, Graham S: Allergy-related diseases and cancer: an inverse association. Am J Epidemiol. 1985, 122: 66-74.CASPubMedGoogle Scholar46.Jensen-Jarolim E, Achatz G, Turner MC, Karagiannis S, Legrand F, Capron M, Penichet ML, Rodriguez JA, Siccardi AG, Vangelista L, Riemer AB, Gould H: AllergoOncology: the role of IgE-mediated allergy in cancer. Allergy. 2008, 63: 1255-1266. 10.1111/j.1398-9995.2008.01768.x.CASArticlePubMedPubMed CentralGoogle Scholar47.Sherman PW, Holland E, Sherman JS: Allergies: their role in cancer prevention. Q Rev Biol. 2008, 83: 339-362. 10.1086/592850.ArticlePubMedGoogle Scholar48.Harvard report on cancer prevention: Causes of human cancer. Genetic susceptibility. Cancer Causes Control. 1996, 7 (Suppl 1): 13-14.Google Scholar49.Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH: Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst. 1994, 86: 1600-1608. 10.1093/jnci/86.21.1600.CASArticlePubMedGoogle Scholar50.Kerber RA, Slattery ML: Comparison of self-reported and database-linked family history of cancer data in a case–control study. Am J Epidemiol. 1997, 146: 244-248. 10.1093/oxfordjournals.aje.a009259.CASArticlePubMedGoogle Scholar51.Love RR, Evans AM, Josten DM: The accuracy of patient reports of a family history of cancer. J Chronic Dis. 1985, 38: 289-293. 10.1016/0021-9681(85)90074-8.CASArticlePubMedGoogle Scholar52.Ligier K, Belot A, Launoy G, Velten M, Bossard N, Iwaz J, Righini CA, Delafosse P, Guizard AV: Descriptive epidemiology of upper aerodigestive tract cancers in France: incidence over 1980–2005 and projection to 2010. Oral Oncol. 2011, 47: 302-307. 10.1016/j.oraloncology.2011.02.013.ArticlePubMedGoogle ScholarPre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/13/560/prepubDownload referencesAcknowledgementsICARE study was supported by the French National Research Agency (ANR), the French Agency for Food, Environmental and Occupational Health and Safety (ANSES), the French Institute for Public Health Surveillance (InVS), the Foundation for Medical Research (FRM), the Foundation of France, the Agency for Research on Cancer (ARC), the French Ministry of Work, Solidarity and Public Function (Direction Générale du Travail), and the Ministry of Health (Direction Générale de la Santé). L. Radoï was supported by the French National Cancer Institute (InCA), grant n° 2009–349 for this work.Author informationAffiliationsCentre for Research in Epidemiology and Population Health (CESP), Inserm U1018, Epidemiology of Occupational and Social Determinants of Health Team, F-94807, Villejuif, FranceLoredana Radoï, Sophie Paget-Bailly, Diane Cyr, Gwenn Menvielle, Annie Schmaus, Matthieu Carton & Danièle LuceUniversity Versailles St-Quentin, F-78035, Versailles, FranceLoredana Radoï, Sophie Paget-Bailly, Diane Cyr, Gwenn Menvielle, Annie Schmaus, Matthieu Carton & Danièle LuceCentre for research in Epidemiology and Population Health (CESP), Inserm U1018, Environmental Epidemiology of Cancer Team, F-94807, Villejuif, FranceFlorence Guida, Sylvie Cénée, Marie Sanchez & Isabelle StückerUniversity Paris-Sud, UMRS 1018, F-94807, Villejuif, FranceFlorence Guida, Sylvie Cénée, Marie Sanchez & Isabelle StückerCalvados Cancer Registry, F-1400, Caen, FranceAnne-Valérie GuizardHérault Cancer Registry, F-34298, Montpellier, FranceBrigitte TrétarreInserm U1085, Irset, Faculté de Médecine, Campus de Fouillole, BP 145, 97154, Pointe-à-Pitre, Guadeloupe French West IndiesDanièle LuceCorresponding authorCorrespondence to Danièle Luce.Additional informationCompeting interestThe authors declare that they have no conflict of interest.Authors’ contributionsDL and LR conceived and designed the current study and drafted the manuscript; LR and DC analyzed the data; DL and IS are the principal investigators of ICARE, conceived the study, designed the questionnaire, and coordinated the original collection of the data. AS, DC, SC, MS, AVG and BT contributed to data collection and quality control; SPB, FG, GM, MC contributed to the statistical analysis. All authors participated to data interpretation and critical revision of the manuscript. All authors read and approved the final manuscript.Rights and permissionsReprints and PermissionsAbout this articleCite this articleRadoï, L., Paget-Bailly, S., Guida, F. et al. Family history of cancer, personal history of medical conditions and risk of oral cavity cancer in France: the ICARE study. BMC Cancer 13, 560 (2013). Family history of cancer, personal history of medical conditions and risk of oral cavity cancer in France: the ICARE studyDownload citationReceived18 January 2013Accepted03 November 2013Published28 November 2013http://DOIhttps://doi.org/10.1186/1471-2407-13-560Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkKeywordsFamily historyMedical conditionsOral cavity cancerRisk factorsCase–control studyDownload PDFBMC CancerISSN: 1471-2407Contact usSubmission enquiries: Access here and click Contact UsGeneral enquiries: [email protected] more on our blogsReceive BMC newslettersManage article alertsLanguage editing for authorsScientific editing for authorsPoliciesAccessibilityPress centerSupport and ContactLeave feedbackCareersFollow BMCBMC Twitter pageBMC Facebook pageBMC Weibo pageBy using this website, you agree to our Terms and Conditions, Privacy statement and Cookies policy. 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ClassificationImmunoglobulin E (IgE)-mediated food allergies are divided into primary and secondary food allergies, which can vary in terms of their course.Primary food allergies primarily occur as a result (most likely) of gastrointestinal sensitization to predominantly stable food allergens (glycoproteins).A secondary food allergy develops after primary sensitization to airborne allergens (e. g., pollen allergens) with subsequent reactions (due to cross-reactivity) to structurally related often labile allergens in (plant) foods.1.2. Prevalence of food allergiesThe prevalence of food allergies varies from region to region and has risen in some countries in recent years. Thus, the prevalence of peanut and tree nut allergy increased three-fold in the US over the last decade. A food allergy results in a reduction in the quality of life of affected individuals and can follow a lethal course in rare cases [15]. In order to assess the:incidence,prevalence,current developments,potential risks andprognostic factors ...of food allergy in Europe, studies aimed at answering these questions and published in the period between 2000 and 2012 were evaluated in a meta-analysis [16]. The point prevalence of self-reported food allergy was approximately six times higher compared with food allergy tested using oral food challenge. The prevalence of primary food allergy was higher in children compared with adults. On the other hand the increased prevalence of secondary food allergies due to cross reactions with inhalation allergens can also be attributed to an increased awareness and improved diagnosis in recent years.Only a few studies on the epidemiology of food allergies in Germany are available. A study from 2004 revealed a prevalence of food allergy of 3.7 % in adults [17] and 4.2 % in children [18], as verified by double-blind, placebo-controlled oral food challenge. A recent study on adult health in Germany (DGES) conducted between 2008 and 2012 revealed a lifetime prevalence of food allergy of 6.4 % in women, 2.9 % in men and as 4.7 % for the entire adult cohort (95 % confidence interval, 4.1–5.4) [19].Prevalence of food allergy in Germany:Suspected: ~20 %Confirmed by oral food challenge (2004):Children: 4.2 %Adults: 3.7 %1.3. Risk FactorsAt present, there are no consistent risk or prognostic factors for the development or outcome of food allergy. However, the following factors influence the prevalence of food allergy:sex and agePlace of residence/geographic locationFamily history of atopyConcomitant allergic diseasesFrom a geographical perspective, the highest prevalence of food allergy in children compared with adults was in North-West Europe. A lower prevalence of self-reported and confirmed food allergy was found in Southern Europe. The authors of the meta-analysis recommend that data on the prevalence of food allergy should be interpreted with caution due to the heterogeneity of the studies and/or methodological or diagnostic differences within one, and between (different) geographical regions of Europe.The prevalence of food allergy is challenging to determine for a variety of reasons:presence of augmentation factors (factors that promote the onset of food allergy symptoms)lack of reproducibility of convincingly described symptomspresence of hidden foodstuffs and of novel foodsinsufficient knowledge of threshold valuesinadequate consideration of individual sensitization profilesnatural tolerance development and new onset of allergies at different ages in life1.4. PrognosisData on the course of food allergies show that milk protein allergy in early childhood has a good prognosis for the spontaneous tolerance development, while peanut and tree nut allergies tend to persist into adulthood. Further studies are required in the future to define the long-term prognosis of food allergy.1.5. Primary triggers of food allergies according to ageThe most frequent triggers of food allergy in children and adolescents include: milk and hen’s egg, soy, wheat, peanut and tree nuts. In adults pollen-associated food allergy is more prevalent and mostly induced by apple and other pome and stone fruits, including shell fruits (see also Tab. ​Tab.6),6), vegetables (celery, carrots), and shellfish. The profile of food allergens that trigger severe allergic reactions is shown in Fig. ​Fig.11.Fig. 1Food allergens as triggers in different age groups [20] (n=665, children and adolescents aged 0–17 years, adults from 18 years). Cases from the anaphylaxis register (1 January 2006 to 31 March 2013)ChildrenAdolescents and adultscow‘s milk, hen‘s egg, peanut, wheat, soy, nuts, fishpollen-associated food allergens (e.g., apple, nuts, soy, celery, carrot, bell pepper, spices), nuts and oilseeds (e. g., sesame), peanut, fish and crustaceans, cow‘s milk, hen‘s egg, latex-associated food allergens (e. g., banana, avocado, kiwi, fig), mammalian meatFood allergy prevalence is age-dependent. A study on food allergy prevalence in Germany shows a prevalence of 4.2% in children and 3.7% in adults.strong consensusIgE-mediated food allergies are differentiated into primary (predominantly in early childhood) and secondary (predominantly pollen-related) allergies, which follow courses of varying severity.consensusFood allergies can significantly reduce the quality of life and may be lethal in rare cases.consensusWorm, JappeGo to:2. Food allergy preventionWhich measures are capable of influencing/reducing the occurrence of a food allergy?The goal of primary prevention is to reduce the risk of allergic sensitization and allergic disease. To achieve this, causal or predisposing factors are either altered or an individual‘s tolerance raised. In terms of the prevention of allergic diseases, a small number of recommendations apply exclusively to high-risk individuals whose father, mother, and/or siblings are already affected by allergic disease. Most recommendations are also appropriate for non-high-risk individuals.The German evidence- and consensus-based S3-guideline on allergy prevention in Germany from 2004 was updated in 2009 [21] and 2014 [22]. The recommendations cover following guideline areas:breastfeedingmother and child nutrition,exposure to inhalation allergens or indoor and outdoor air pollutants, including tobacco smoke,keeping animals,vaccinations andmode of delivery in childbirth.The following individual recommendations (level of recommendation: A–C) related to these areas are:Full breastfeeding for the first 4 months (A)Hydrolyzed formulas to be used in cases where high-risk infants up to the age of 4 months are not, or only insufficiently, breastfed (A)No dietary restrictions in mothers (during pregnancy/breastfeeding) (A) and infants (B) as a means of primary preventionNo delay in the introduction of solid foods (A)Fish to be consumed by mother and child (B)Avoidance of overweight/obesity (A)No specific measures to reduce house dust mite allergens as a means of primary prevention (B)No restrictions on the keeping of domestic pets in at-risk children, no acquisition of cats in at-risk children (B)Avoidance of indoor conditions supporting to the development of mold (high humidity, insufficient ventilation), and minimization of exposure to indoor air pollutants (B)Minimization of exposure to motor vehicle emissions (B)Avoidance of active and passive exposure to tobacco smoke—as early on as during pregnancy (A)Vaccination according to STIKO recommendations for all children, irrespective of allergy risk (A)infants delivered by caesarean section have an increased risk of allergy (B)There is evidence that the consumption of fruit and vegetables (a so-called Mediterranean diet), ω-3-fatty acids (FA) (or a good ω-3:ω-6 ratio), and milk fat has a preventive effect on atopic diseases.Probiotics have only been shown to have a preventive effect on atopic dermatitis. Due to the heterogeneity of bacterial strains used and study designs applied, it is not possible to make recommendations on specific preparations, modes of administration, or duration and time of http://use.As yet, prebiotics have only been shown to have a preventive effect on atopic dermatitis. Due to the small number and heterogeneity of studies, no recommendations can be made.Associations described between the use of antibiotics, paracetamol, or acetaminophen and atopic disease cannot be reliably interpreted and no causal link has been found between the use of these pharmaceutical drugs and the development of atopic disease(s).There is evidence that adverse psychosocial factors (e. g., stressful life events) during pregnancy and childhood can contribute to the onset of atopic disease.In addition to the S3-guideline, there is evidence that the use of antacids can promote the risk of sensitization and increase the severity of food allergy [23].Section in its entirety strong consensusBeyer, ReeseGo to:3. Symptoms and the differential diagnosis of food allergy3.1. Clinical symptomsWhat are the most common symptoms of a food allergy?A variety of symptoms may be elicited by an IgE-mediated food allergy depending on [24, 25]:Use (site of exposure) of a food proteinUnderlying diseaseFrequency of exposureDoseMost symptoms are not observed exclusively in food allergy and can be caused by other diseases.Although the immune system is most commonly exposed to food proteins via oral/gastrointestinal routes, exposure can also take place via the following routes:Percutaneous (via the skin, e. g., contact urticaria)Inhalation (via the respiratory tract, e.g., baker‘s asthma, see Sect. 7 below)Parenteral (via the vascular system, e. g., contamination of injection solutions with food proteins).The exposure route is relevant in terms of clinical symptoms. A variety of symptoms – often in combination – can be observed depending on the organ system affected (modified according to [26]) (Tab. ​(Tab.2,2, Tab. ​Tab.33).Target organSymptomsSystemic, circulatoryAnaphylaxisHypotension, shockTachycardia (in rare cases, bradycardia in anaphylaxis)Drowsiness, dizzinessSyncopeSkinErythema (transient, flush)Eczema (exacerbation)UrticariaItchingAngioedemaRashEyesItching(conjunctival injections)LacrimationPeriorbital edemaUpper respiratory tractNasal congestionItchingrunny nose (rhinorrhea)Laryngeal edema, stridorHoarsenessDry coughLower respiratory tractSwelling of the lips, tongue, and/or gums (angioedema)Oral and/or pharyngeal itching (pruritus)Swelling of the tongueGastrointestinal tractNauseaVomitingColic-like abdominal painGastroesophageal reflux (GER)DiarrheaNauseaVomitingAbdominal painGastroesophageal reflux (GER), dysphagia, and food bolus impactionLoss of appetite and refusal to eatDiarrhea, malassimilationHematochezia (blood in stools)Failure to thrive and weight lossSymptoms of IgE-mediated food allergies are diverse and affect a variety of organ systems (most notably skin and mucosa, less often the gastrointestinal tract, respiratory tract, and cardiovascular system).strong consensusIn order to diagnose food allergy, a clear and reproducible association between symptoms and the intake of a defined food and an improvement in symptoms upon avoidance in conjunction with IgE sensitization needs to be present.strong consensusIn the case of intermittent tolerance to foods, augmentation factor-dependent allergies such as food-related exercise-induced anaphylaxis need to be taken into consideration.consensusClassen, Lange, Rabe, KoletzkoIn the case of suspected food allergy, it is important to consider in the differential diagnosis chronic inflammatory diseases, carbohydrate malabsorption and functional or somatoform disorders.strong consensusstrong consensusDepending on patient symptoms and age, other diseases need to be taken into consideration in the differential diagnosis of suspected food allergy.strong consensusA (pediatric) gastroenterologist should be involved in the diagnostic work-up in the case of suspected non-IgE-mediated gastrointestinal intolerance reactions.consensusClassen, Lange, Rabe, Koletzko3.2. Manifestations and differential diagnosesWhich other diseases can cause the symptoms of a food allergy?What are the clinical manifestations of a food allergy?Foods can cause a variety of diseases. These are based on differing pathophysiological mechanisms and can involve different, sometimes multiple, organ systems (see also Sect. 7, Tab. ​Tab.1717).ImmunopathologyDisease/symptomsClinical characteristicsTypical age groupPrognosisIgE-mediatedContact urticaria syndrome (grade I–IV)Triggered by predominantly occupation-related skin contactAdults, occupationally exposed individualsDependent on the triggering food and possible avoidance measuresOccupational obstructive airway disease (including allergic rhinopathy) caused by allergenic substancesPredominantly workplace-related airway symptoms due to inhalation allergen exposureAdults, occupationally exposed individualsDependent on the triggering food and possible avoidance measuresMixed IgE- and cell-mediatedProtein contact dermatitisTriggered on the hands predominantly by work-related skin contactAdults, occupationally exposed individualsMore severe effects and less favorable prognosis compared with skin disorders of other originNon-immunologicalNon-immunological contact urticariaTriggered on the hands predominantly by work-related skin contact with benzoic acid, sodium benzoate, sorbic acid, abietic acid, nicotinic acid ester, cinnamic acid, cinnaminic aldehyde, and balsam of PeruAdults, occupationally exposed individualsIn contrast to IgE-mediated contact urticaria, generally restricted to the area of contactOpen in a separate windowTab. ​Tab.44 provides an overview of food allergy manifestations and differential diagnoses.ImmunopathologyDiseaseClinical characteristicsTypical age groupPrognosisIgE-mediatedAcute urticaria/angioedemaElicited by ingestion or direct skin contactChildren > AdultsDepending on the triggering foodRhinoconjunctivitis/bronchial asthmaAccompanies food protein-induced allergic reactions, on rare occasions airway symptoms (exception: inhalation exposure to aerosolized food protein, often occupational)Infant > adult, with the exception of occupational diseasesDepending on the triggering foodAnaphylaxisRapidly progressive multisystem reactionAll agesDepending on the triggering food and underlying diseaseDelayed food-induced anaphylaxis to mammalian meat [27]Anaphylaxis 3–6 s following ingestion; triggered by antibodies to galactose-α-1,3-galactoseAdults > ChildrenUnclearFood- and risk factor-induced anaphylaxisFood only triggers anaphylaxis in the presence of augmentation factors such as exertion, as well as alcohol or acetylsalicylic acid (ASA) before or after food intakeOnset in late childhood/adulthoodProbably permanentSecondary allergic cross-reactions (predominantly pollen-associated food allergies)Oropharyngeal irritation; mild edema restricted to the oral cavity More rarely, perioral or generalized urticaria Airway symptoms (cough); In rare cases, systemic reactions (including anaphylaxis) in some pollen-associated allergiesOnset following pollen-allergy manifestation (adult > young child)May persist; may vary seasonallyGastrointestinal allergic immediate-type reactionsRapid-onset nausea following ingestion, followed by abdominal colic and diarrhea laterAll agesDepending on the triggering foodMixed IgE- and cell-mediatedAtopic eczema/dermatitisAssociated with food in 30 %–40 % of children with moderate/severe eczemaInfants > children > adultsIn general, tolerance developmentEosinophil-associated gastrointestinal disorders (EGID)Symptoms vary: depending on the affected segment of the gastrointestinal tract and the degree of eosinophilic inflammationAll agesLikely to be persistentCell-mediatedFood protein-induced proctitis/proctocolitis Food protein-induced enterocolitis syndrome (FPIES)Mucous, bloody stools in infants Acute exposure: severe manifestations ranging from vomiting, (bloody) diarrhea, and exsiccosis to shock Chronic exposure Vomiting, diarrhea, failure to thrive, lethargy Re-exposure following avoidance: vomiting, diarrhea, hypotension 1–3 h following ingestionInfants Infants – young childrenLikely to be persistent In general, tolerance development In general, tolerance evelopmentFood protein-induced enteropathyDiarrhea, vomiting, failure to thrive, edema; no colitisInfants – Young children > AdultsIn general, tolerance developmentCeliac diseaseMultiple manifestations, mono-, oligo-, and polysymptomatic, triggered by gluten in the case of genetic predispositionAll agesPersistent (necessitating strict, lifelong gluten avoidance)Non-allergic (non-immunological intolerance)Carbohydrate malassimilation/malabsoption (lactose, fructose, sorbitol, in rare cases: sucrose, glucose-galactose)(Osmotic) diarrhea, meteorism, abdominal pain 1–4 h following intake, possibly also obstipationLactase deficiency typically from school age, otherwise all ages Fructose malabsorption/sorbitol: all ages, very rarely: congenital lactase deficiency, glucose-galactose intolerance, sucrose-isomaltase malabsorptiongenerally persistent (lactose, glucose-galactose); fructose, sorbitolOpen in a separate windowNon-allergic mechanisms: Food additives and natural flavorings can also potentially activate mast cells and imitate clinical symptoms of an IgE-mediated food allergy: for example, G-protein-coupled receptor activation, changes in eicosanoid metabolism, and increased mediator production/expression have been postulated. Isolated cases of non-allergic food intolerance reactions triggered by natural flavorings, sulfur compounds, benzoic acid compounds, histamine-containing foods, and glutamate have been described. Augmentation factors may be necessary to elicit a reaction, thus these should be considered where oral challenge is negative.It is unlikely that salicylate-containing foods are of any relevance in acetylsalicylic acid (ASA) intolerance, since salicylic acid is not commonly found in foods [28]; however, this has not been sufficiently researched.Go to:4. Food allergy diagnosisHow can one reliably diagnose a food allergy?Approach in suspected food allergy: In suspected IgE-mediated food allergy, diagnosis is based on a number of components (Fig. ​(Fig.22):Fig. 2Diagnostic approach in suspected food allergy: sensitization often detected in adults using skin tests (left), in children preferably using specific IgE determination (right; see text for additional details)Patient history (including diet and symptom protocols where appropriate) (4.1.)Sensitization test (colloquially known as an „allergy test“)IgE determination (Sect. 4.2) and/orSkin prick test (Sect. 4.3)Determining clinical relevance (interpretation)Plausibility based on clinical information (in the patient history)Where appropriate, diagnostic elimination diet andOral challenge testing (Sect. 4.4)Test sequence and test reagents are selected on the basis of:a) Patient historyb) Patient agec) Testing methods available (discussed in subsections)Diagnostic tests identify sensitization. This is achieved by:Directly determining allergen-specific IgE to food extracts/allergens in serum (Sect. 4.2), or bypositive skin testing (skin prick test) (Sect. 4.3) with food (extracts) as indirect evidence of functional (i.e., capable of cross-linking) allergen-specific IgE on skin mast cells.The qualitative results (positive vs. negative) of IgE tests and skin prick tests allow the following interpretation:A negative result excludes sensitization.A positive result indicates sensitization which, however, is only clinically relevant in the presence of corresponding symptoms.A single test (IgE test or skin test) may be sufficient to verify a sensitization to food. It is common for a number of tests to be used to detect sensitization (Fig. ​(Fig.2).2). Results are not always consistent; in such cases, a positive result is more likely to be correct than a (false) negative result. Consistent results (concordant positive or negative) increase diagnostic accuracy, particularly if mostly different food reagents (native preparation, extracts, single allergens) are used in skin or IgE tests.Test interpretation: The patient history is of central importance in the interpretation of sensitization tests: A food allergy can only be diagnosed or excluded in the case of clear concordance between clinical patient information and test results (skin prick test/IgE de-termination). In the case of absent or insufficient concordance (e. g., due to unclear or inadequate patient history), clinical relevance should be investigated using oral challenge (Fig. ​(Fig.2;2; Sect. 4.4).The term „allergy test“ (for skin or IgE tests) is in this context ambiguous and represents the greatest cause of misinterpretation of diagnostic results: A positive result, e. g., to food (i. e., sensitization) can only be successfully interpreted when the clinical reaction is known.Approximately half of the atopic sensitizations detectable in a population are genuinely associated with symptoms and thus of clinical relevance. Thus, all sensitization tests show unsatisfactory diagnostic specificity (approximately 50 %) and limited positive predictive value (PPV) strongly, depending on the respective allergen source and the prevalence of food allergy in the cohorts investigated.In of gastrointestinal allergic manifestations, local diagnostic measures can be considered, such as mucosal or endoscopic provocation tests and endoscopic lavage.Specific tests for IgE sensitization should be guided by patient history.strong consensusIgE sensitization to foods and aeroallergens should be performed by means of specific IgE determination and/or skin prick testing.consensusSpecific IgE determination and skin prick testing support the diagnosis of food allergy in conjunction with patient history and/or food challenge.strong consensusThe detection of sensitization by means of specific IgE determination or skin prick testing does not prove the clinical relevance of the tested food and should not, in isolation, prompt its therapeutic elimination.strong consensusFailure to detect sensitization (negative specific IgE/skin prick test) often, but not always, excludes a clinically relevant IgE-mediated food allergy.consensusKleine-Tebbe4.1. Patient history and diet/symptom protocolsHow important is the history of patients in suspected food allergy?Which aspects of the patient history need to be considered in suspected food allergy?4.1.1. Practical approach to history-takingAllergy history-taking in suspected food allergy follows the general principles of interviewing. Providing patients with a special questionnaire prior to their initial appointment is helpful; patients should either bring the completed questionnaire to their appointment or complete it in the waiting room.History-taking (Tab. ​(Tab.5)5) includes family history, personal history and specific dietary history.Patient historyPersonal patient historyKnown allergic diseases Medications Physical exercise Acute infectious diseases Psychological stressorsFamily historyAllergic diseases in first-degree relativesSymptoms and specific triggersWhen Where In response to what How long How often RepeatedlyDietary historyAvoidance measures and extent thereofDietary and symptom diaryDocumenting food and symptomsThe times, places, and situations in which reported symptoms occur should be recorded. It is particularly important to establish whether the patient experiences periods of complete freedom from symptoms.4.1.2. Supporting measuresA diet- and symptom diary helps patients to observe their habits and symptoms. Particularly if symptoms are permanently apparent, it is helpful for patients or their parents to keep a record over a period of 2–3 weeks Besides the intake of food, but also beverages, confectionery, chewing gum, etc., symptoms occurring in temporal relationship to this intake should be recorded. Recordings are evaluated by a dietician with experience in allergy, or an allergist.Drug use should also be recorded in the diary. Symptoms should cover the type and intensity and date, time, duration it present and particular features (e. g., restaurant food). Once a diagnosis has been made, the further diagnostic and therapeutic approach is planned with the help of a follow-up patient history. In this way it is possible to qualify or confirm the relevance of existing (or absent) sensitizations and facilitate the decision-making process on challenge testing or other measures. It is also important to bear in mind that some medications [e. g., proton pump inhibitors (PPI) or alkylating drugs) can promote the development of sensitization [29].4.1.3. Consideration of augmentation factorsAugmentation factors should also be taken into consideration in the patient history. These can magnify an allergic reaction and, in some cases, need to be present in order to facilitate the onset of symptoms occur (e. g., in wheat-dependent exercise-induced anaphylaxis). The most widely known augmentation factors include:physical activity andthe use of non-steroidal anti-inflammatory drugs (NSAID)Moreover, alcohol, pyrexia, acute infections and allergic symptoms during the pollen season have also been described as augmentation factors [30].A detailed patient history should build the basis for the diagnosis of food allergy.consensusA structured patient history should take: time course, symptoms, family history, comorbidities and the presence of other allergic diseases into consideration.strong consensusA diet- and symptom log is supportive.strong consensusWorm, Reese, Klimek4.2. Triggering allergens and in vitro diagnosticsHow to determine the severity of a food-related allergic reaction?What are helpful indications for sIgE determination?How to classify the relevance of diagnostic methods using single allergens?How relevant are sensitizations to specific allergens?Which are the most important allergens in food allergy?What needs to be taken into consideration in serological diagnosis?4.2.1. Serological IgE determination to detect sensitizationAllergen-specific serum IgE to food allergens indicates sensitization. The absence of specific IgE (generally) excludes sensitization if the test covers all relevant allergens.The results of logarithmically distributed specific IgE concentrations can differ from one another depending on:ManufacturerTest designReagentsAllergen(extract)s (most important)The following allergens are used for IgE testing:Individual foods (allergen sources, Tab. ​Tab.66)A combination of different foods (screening or panel test)Single allergens (Tab. ​(Tab.77–9, additional sources of information in Tab. ​Tab.10)10) [32].AllergenA molecule (protein, e. g., major allergen Gad c 1 from cod, more rarely a carbohydrate component) that elicits an allergic immune responseAllergen extractA mixture of allergenic and non-allergenic components extracted from an allergen source (e.g., fish allergen extract)Allergen source/carrierOrigin/source material of the allergens (e.g., fish)α-GalGalactose-α-1,3-galactose, a disaccharide as the cause of severe anaphylaxis to mammalian meat, gelatin, and biologicalsAra h 22S albumin, a peanut storage protein associated with severe systemic reactions in peanut allergyApi g 1Bet v 1-homologous celery allergen responsible for birch pollen-associated cross reactionsBet v 1Immunodominant major allergen in pollen and birch (Betula verrucosa)Bet v 2Birch pollen profilin which, as a panallergen in numerous pollen and plant-based foods, can be responsible for broad cross reactivity and hamper proper diagnosticsCCDCross-reactive carbohydrate determinants: N-glycan epitopes which, as panallergens, are responsible for broad cross-reactivityCor a 1.04Bet v 1-homologous hazelnut allergen responsible for birch pollen-associated cross reactionsDau c 1Bet v 1-homologous carrot allergen responsible for birch pollen-associated cross reactionsGad c 1Major cod allergen (Ca2+ transport protein, parvalbumin, most important fish allergen)Gly m 4Bet v 1-homologous soy allergen responsible for birch pollen-associated, partially severe cross reactionsCross reactiveImmunological response based on the similarity between molecular structures not responsible for the initial sensitizationLTPLipid transfer proteins: heat- and digestion-stable allergens of plant originMal d 1Bet v 1-homologous apple allergen responsible for frequent birch pollen-associated, mostly oropharyngeal cross reactionsMUXF3Name given to the structure of a carbohydrate side chain made up of plant glycoproteins and allergens that can potentially be bound by IgE antibodies, a specific type of CCD (see above)OleosinsLipophilic and heat-stable allergens in nuts and oilseedsPen a 1Tropomyosin (muscle structure protein) in the shrimp with homologous proteins in other arthropods and the cause of cross reactionsPR-10Pathogenesis-related protein family 10; bet v 1-homologous protein involved in plant defense (e.g., in tree pollen, foods)Pru p 3Peach LTP responsible for systemic reactions in patients in the Mediterranean regionRecombinantProduced using genetically altered (micro-)organismsRecombinant allergenAllergenic protein frequently produced in Escherichia coli without the carbohydrate side chains found in native allergensSensitizationSusceptibility to allergy (only relevant in the presence of corresponding symptoms)Tri a 19ω-5-Gliadin in wheat responsible for systemic reactions and exercise-induced anaphylaxis in wheat allergyOpen in a separate windowProtein familiesParvalbuminsTropomyosinsLysozymes/α-lactalbuminsOther proteins (various families)Hen‘s eggGal d 4(lysozyme C)Gal d 1(ovomucoid, trypsin inhibitor)Gal d 2(ovalbumin, serpin)Gal d 3(ovotransferrin, conalbumin)FishGad c 1Cyp c 1Ani s 3bCrustaceans/molluscsHom a 6Cha f 1Hom a 1Met e 1Pen a 1Cow‘s milkBos d 4 (α-lactalbumin)Bos d 5 (β-lactoglobulin, lipocalin)Bos d 6 (bovine serum albumin)Bos d 8 (casein)Open in a separate windowa Allergen sources (left column) with single allergens (table columns) and their protein families (table header)b Severe allergic reactions following the consumption of fish infected by the herring worm (Anisakis) have been describedc Bold: already available for in vitro diagnosis, normal type: not yet available for differentiated diagnosisWeb linkShort descriptionwww.allergen.orgOfficial database of the IUIS Allergen Nomenclature Sub-committee with simplified search functionwww.allergenonline.orgFood allergen database of the University of Nebraska in Lincoln, Food Allergy Research and Resource Program (FARRP); carefully maintained records sorted according to taxonomic affiliation of the allergen sourceswww.allergome.orgLargest database of allergen molecules, initiated by the Italian allergologist, Adriano Mari, and his team; some of the identified single allergens were included prior to their official http://namingwww.meduniwien.ac.at/allergens/allfam/Database of allergen families (protein families) of the Vienna Medical University, Institute for Pathophysiology and Allergy Research at the Center for Pathophysiology, Infectology, and Immunologywww.allergyeducation-ma.comShort animated presentation made by a diagnostic manufacturerThe diagnostic suitability is evaluated separately according to the allergen source and test procedure.4.2.1.1. Indication for IgE determinationThere are a number of different indications for in vitro diagnosis [33] depending on:age,symptoms andsuspected allergen source (Tab. ​(Tab.66).Suspicion/exclusion of a food allergy: Specific IgE determination is helpful if food allergy is suspected or should be excluded. This indication requires that the allergen sources or allergens used in the test are fully represented and are capable to detect potentially present IgE antibodies.Panel tests for specific IgE (e. g., to peanut, fish, chicken protein, cow milk protein, soy, and wheat) make it possible to reasonably exclude as as basis for further or detect sensitization. Thus, they serve as a for a further detailed breakdown of single allergen sources. Broad screening panels in the absence of a reasonable suspicion of food allergy are not recommended.Severe allergic reactions to foods: Determining specific IgE to the foodstuff suspected (or to be excluded) in severe anaphylactic reactions is preferred and skin testing should be performed after consideration of the individual risk:benefit ratio.Suspected sensitization to foods suitable for skin testing: Specific IgE determination is recommended in such cases where skin testing is not suitable to detect sensitization (e. g., skin-irritating foods such as spices).Conditions that preclude skin testing or its interpretation: Specific IgE determinations are helpful if skin testing is not suitable. Such cases involve urticaria factilia or active skin disease in the test area in a given Patient or the use of drugs that affect skin testing. Analysis of specific serum IgE to allergenic foods is often determined in infants and young children instead of performing skin tests.Common food allergen sources with low potential risk: Mild clinical reactions (e. g., oropharyngeal symptoms in pollen-associated food allergy) can be tested in the usual diagnostic work up, i. e., patients history, skin testing, in vitro diagnosis. Sensitizations in birch pollen-associated food allergy should be tested by native prick-to-prick testing, since commercially available extracts do not contain the relevant allergens sufficiently. Screening (including serological tests) without specific suspicion of food allergy, e. g., of all fruit and vegetable types or the available single allergens in birch pollen-associated cross-sensitization, is not recommended [3].4.2.1.2. Definitions and concepts for allergen selectionThe potential advantages and disadvantages of in vitro diagnostics using extracts or single allergens need to be defined separately for each allergen source or single allergen [35] (see information in Tab. ​Tab.1010).The following arguments support the use of single allergens (Tab. ​(Tab.1111):Test sensitivity (LoQ)SpecificityAnalytical+ Smallest quantity of a test substance that can be precisely determined (lower LoQ)+ Ability of a test to measure a specific substance rather than others in a test (analytical selectivity)SensitivitySpecificityDiagnostic(+) Proportion of affected individuals identified correctly (i.e., positive result) as affected prior to testing(+) Proportion of healthy individuals identified correctly (i.e., negative result) as healthy prior to testing*Components in IgE diagnostic testing increase test sensitivity (lower limit of quantitation, LoQ), particularly when they are underrepresented or absent in extracts. They increase analytical specificity, since only part of the allergen-specific IgE repertoire is identified and, e.g., cross reactivity due to extracts of complex composition is avoided. It is sometimes also possible to improve diagnostic test characteristics with regard to clinical symptoms (diagnostic sensitivity and specificity) (see text for more details).Increased test sensitivity [lower limit of quantitation (LOQ)] [36] due to certain single allergens, particularly if they are underrepresented or absent in the (food) extract (examples: soy protein Gly m 4 [37], wheat gluten Tri a 19, apple protein Mal d 1, galactose-α-1,3-galactose, a sugar epitope of mammalian meat).Increased test discriminatory power (analytical specificity or selectivity) with single allergens from allergen sources made up of complex mixtures of multiple allergens and associated with increased clinical risk (examples: Ara h 2 from peanut, Pru p 3 from peach, Cor a 9 and 14 from hazelnut, Act d 1 from kiwi).The detection of IgE to typical cross-reactive allergen molecules facilitates interpretation in the case of low analytical specificity of extracts (cross reactivity) (examples: Bet v 1 or homologs, Phl p 12 or Pru p 4 as profilin, Pru p 3 as lipid transfer protein [LTP], cross-reactive carbohydrate determinant [CCD] components MUXF3).Current reimbursement restrictions on IgE measurements can result in unacceptable limitations regarding a more extensive screening which may be needed in more complex cases of food allergy.A lower LoQ when using single allergens in IgE diagnostics does not necessarily increase diagnostic sensitivity. Where this is the case diagnostic specificity can be lower. (Tab. ​(Tab.1111).Both parameters, diagnostic sensitivity and specificity, can result in difficulties regarding the interpretation of specific IgE diagnostic methods: A positive IgE finding, reflecting sensitization without information on previous history, cannot per se predict clinical reactions in food allergie individuals. Therefore , international guidelines on allergen-specific IgE test methods [38] no longer require diagnostic sensitivity and specificity to be given, but are replaced by analytical parameters. Thus, the use of single allergens for IgE determination is justified, most notably by their greater test sensitivity (lower LoQ) and analytical specificity: Where single allergens are capable of improving in vitro diagnosis, their use is helpful and recommended from an allergological perspective.4.2.1.3. Foodstuffs as allergen sources and their allergensFoodstuffs are complex allergen sources and contain a variety of (glyco)proteins, the actual allergens. A relationship is therefore formed by the biological taxonomy of the foodstuffs in question and via biochemical similarity of the allergens contained. The relevance of allergen sources (Tab. ​(Tab.6)6) is related to the age of the affected patient and depends on regional and personal dietary habits.4.2.1.4. Important plant protein families and their allergensFruit, vegetables, legumes, tree nuts, oilseeds, and cereal contain allergens and can cause sensitization [39].The most important protein families and single allergens in plant foods have now been identified (Tab. ​(Tab.8).8). These are increasingly used for IgE diagnostics (Tab. ​(Tab.8,8, Tab. ​Tab.1212).Protein familiesStorage proteins (protein families, structure)ProlaminsCupinsBet-v-1 homologsLTPProfilinsThaumatinsOleosins2S Albumins7/8S Globulin (vicilin)11S Globulin(legumin)AppleMal d 1Mal d 3Mal d 4Mal d 2PeanutAra h 8Ara h 9Ara h 5Ara h 10 (16 kD)Ara h 11 (14 kD)Ara h 2Ara h 6Ara h 7Ara h 1Ara h 3SpicesBellpepperParsleyPet c 1Pet c 3Cap a 2Pet c 2Cap a 1HazelnutCor a 1Cor a 8Cor a 2Cor a 12 (17 kD)Cor a 13 (14/16 kD)Cor a 14Cor a 11Cor a 9CarrotDau c 1Dau c 3Dau c 4CherryPru av 1Pru av 3Pru av 4Pru av 2KiwiAct d 8Act d 9Act d 2PeachPru p 1Pru p 3Pru p 4CeleryApi g 1Api g 4SesameSes i 4Ses i 5Ses i 1Ses i 2Ses i 3Ses i 6Ses i 7SoybeanGly m 4Gly m 1Gly m 3Gly m 5Gly m 6WheatTri a 14Tri a 12Tri a 19(ω-5-gliadin)Open in a separate windowaAllergen sources (left column) with single allergens (table columns) and their protein families (table header)bBold: already available for in vitro diagnosis; normal type: not yet available for differentiated diagnosisClinical pictureClinical suspicionIgE diagnosticsAnaphylaxis following physical activityExercise-induced wheat allergyTri a 19 (ω-5-gliadin)Pork-cat syndromeAllergy to mammalian serum albuminsFel d 2 or Bos d 6Delayed meat allergy (e. g., urticaria)Sensitization to galactose-α-1,3-galactose (α-GAL)α-GAL (thyreoglobulin)Allergy, e. g., to grapesSensitization to lipid transfer proteins (LTP)Pru p 3 (peach LTP)Oral allergy syndrome (OAS), frequently to nuts, pome and stone fruits, etc., systemic reactions to (native) soy possibleSensitization to Bet-v-1 homologs (PR-10 proteins)Bet v 1 and Gly m 4OAS following uncommon plant foods (melon, exotic fruits such as lychee and citrus fruits)Sensitization to profilinsPru p 4 (or Bet v 2, Phl p 12, Hev b 8)Technical and methodological errors(Reasons for false-positive and false-negative results)_ Poor reagent quality (e.g., allergen extracts or their extraction, coupling, and stability)_ Laboratory errorsInterpretation errors(Reasons for clinically irrelevant results)_ Markedly elevated total IgE and multiple sensitizations_ High detection sensitivity_ Cross-reactive IgE antibodiesIgE, immunoglobulin EProfilins: From a phylogenetic perspective, profilins are strongly conserved proteins and are considered to be clinically less relevant allergens. Sensitizations are, often caused primarily by grass-pollen exposure but, are potentially linked to all pollen and numerous plant foods (e. g., apple, carrot) due to cross reactions. Determination of sIgE against one profilin (e. g., grass pollen profilin Phl p 12, birch pollen profilin Bet v 2, or peach profilin Pru p 4) is usually sufficient for diagnostic purposes. Exotic fruits not belonging to the Bet-v-1 food allergen cluster (e. g., melon, banana, avocado, mango) have been reported to induce oropharyngeal symptoms [3].Bet v 1-homologous PR-10 proteins: Birch pollen allergy in Central Europe is predominantly due to sensitization to the major allergen Bet v 1, a natural plant stress protein (pathogenesis-related protein family 10, PR-10).Similar PR-10 proteins are found in hazel, alder, beech, and oak tree pollen, but also in various types of fruit and vegetables, as well as nuts and legumes (Tab. ​(Tab.8).8). They form the basis for birch pollen-associated cross reactions, e.g., to apple, cherry, peach, and hazelnut, among many others [3]. Due to the low proportion of PR-10 proteins in the total mass and their lack of heat and digestive resistance, symptoms are caused only by raw foods and generally remain restricted to the mouth and throat. In individual cases, severe systemic symptoms may occur, e.g., if large quantities of the food are consumed or due to matrix effects (the PR-10 protein is protected by other food components) (examples: Gly m 4 in soy, more rarely also Api g 1 in celery, Dau c 1 in carrots).Lipid transfer proteins: Systemic reactions induced by fruit, vegetables, nuts, legumes, and cereals can be caused by LTP. Ripe peach can initiate primary sensitization, as described in the Mediterranean region. The structural similarity of peach LTP, Pru p 3, to other heat- and acid-stable LTP can cause cross reactions to other plant foods and to a certain extent independent from the Bet v 1 cluster described (e. g., wine grapes, blueberries, vegetables). The major allergen Pru p 3 is often sufficient to detect sensitization. The clinical relevance of LTP sensitization in terms of plant foods to be avoided in the future needs to be established with the patient on a case-by-case basis. This is achieved on the basis of the patient‘s previous history (clinical reaction) or, in cases of doubt, oral challenge with the suspected LTP-containing foods.Seed storage proteins: Storage proteins are structurally related yet variable, stable and clinically relevant food allergens, e. g., in nuts, seeds, legumes, including peanut, soybean, lupin, and cereals.A distinction is made between 2S albumins from the prolamin and globulins from the cupin superfamilies on the basis of their structure. The globulins contain vicilins (7S globulins) and legumins (11S globulins) (Tab. ​(Tab.8).8). Due to their stable structure and high proportion of the total protein, storage proteins rarely cause problems in extract-based diagnosis. They are associated with an increased risk for systemic symptoms due to their heat and digestive stability. The following storage proteins are well suited for a selective detection/exclusion of sensitization by analytical methods:Gly m 5 and 6 in soy allergyAra h 1, 2, 3, and 6 in peanut allergyCor a 9 and 14 in hazelnut allergyJug r 1 and 2 in walnut allergyBer e 1 in Brazil nut allergySerological cross reactions between storage proteins do not permit predictions of the onset of clinical symptoms.4.2.1.4.1. Other allergens in plant derived foodsCross-reactive carbohydrate epitopes: Numerous plant derived foods are glycoproteins containing CCD (Cross-reactive Carbohydrate Determinants) (e. g., in pollen, plant foods, articulates, molluscs, and certain pathogenic helminths). Their IgE binding is generally clinically irrelevant [41]. Although they do not give rise to positive skin tests, they hamper IgE diagnosis with extracts or natural CCD-bearing single allergens. Specific tests against bromelain, horseradish peroxidase or the N-glycan MUXF (CCD single allergen component of bromelain with no peptide component) are well suited for CCD-specific IgE screening.Oleosins: Oleosins are allergens which are present in high fat plant foods. As lipophilic proteins, they are underrepresented in aqueous extracts of legumes (e. g., peanut), seeds (e. g., sesame), and tree nuts (e. g., hazelnut) They can results in false-negative diagnostic results. In such settings, testing of the native foodstuff in skin tests is suggested.Thaumatins and enzymes: Thaumatin-related proteins are thermo- and digestion-stable plant foods [40], i. e. from cherry (Pru av 2), apple (Mal d 2), kiwi (Act d 2), banana (Mus a 4), peach (Pru p 2), tomato, bell pepper and walnut. They are rarely available for diagnostics (Act d 2 from kiwi, ImmunoCAP ISAC®). The prevalence of sensitizations or clinically relevant reactions is unknown. A similar situation is present for a number of enzymes found in plant foods (e. g., exotic fruits).4.2.1.5. Common animal food allergensAnimal proteins from a variety of allergen sources can also induce food sensitization. These are often heat- and digestion-stable and can cause systemic allergic reactions.Their structural similarity induces serological cross reactions within a protein family. However the clinical relevance cannot be deduced from the test result. Due to complex sensitization patterns and good representation of the proteins, diagnosis using extracts is often sufficient.Hen‘s egg: The most important hen´s egg allergens have been identified (Gal d 1, 2, 3, 4).Sensitizations to the heat resistant major allergen Gal d 1 are frequently associated with persistent hen‘s egg allergy. The failure to detect IgE during the course of hen‘s egg allergy can indicate the development of tolerance. Despite clinically relevant hen‘s egg allergy (also in Gal d 1 sensitization), the majority of affected patients tolerate egg in cooked form.Cow‘s milk: Complex sensitization patterns to predominantly stable cow milk proteins and the fact that these proteins are well represented in cow milk extracts are rationales to use the total extract for diagnostic purposes. Due to their stability, some single allergens, such as Bos d 8 (casein), are associated with persistent cow‘s milk allergy and reactions to processed milk (products). Decreasing or absent IgE may indicate the development of tolerance. Again, the majority of cow‘s milk allergics tolerate cow‘s milk in cooked form.Meat: Allergies to mammalian meat, particularly after consumption of pluck, can be caused by sensitization to serum albumins. Due to high cross reactivity, determining IgE to one representative serum albumin (e. g., Fel d 2 from cat, Bos d 6 from cow) is sufficient.A further source of allergic reactions following the consumption of meat is a carbohydrate epitope (CCD) found in mammals (but not primates): α-Gal. This carbohydrate side chain is responsible for delayed urticarial and severe anaphylactic reactions following the intake of red meat [42]; poultry, on the other hand, is tolerated. In suspected meat allergy, IgE determinations to albumins, α-Gal (o215, ImmunoCAP®, ThermoFisher), and the suspected meat type are helpful.Fish: Reactions following fish consumption are often caused by a major allergen of the parvalbumin group (e. g., Gad c 1 from cod, Cyp c 1 from carp). Since additional species-specific fish allergens can cause sensitization, extract-based diagnosis with the suspected fish type is recommended. The high stability of most fish allergens to heat and digestion, as well as the fact that they make up a large proportion of the total protein, explains their hazardous nature: Even small amounts can be sufficient to trigger systemic reactions.Crustaceans and molluscs: Tropomyosin, a muscle protein with high cross reactivity, is considered an important major allergen in crustaceans and shellfish. In addition to determining this major allergen (e. g., Pen a 1, shrimp tropomyosin), the use of extracts from the suspected animal is recommended due to additional possible allergens. Shrimp can also trigger exercise-induced anaphylaxis. House dust mite allergy sufferers sensitized to tropomyosin, minor allergen Der p/f 10, can react to crustaceans.4.2.1.6. Interpreting serological IgE diagnostic methodsSpecific IgE to food allergens can only be reliably interpreted when the clinical reaction of the patient is known.The following interpretation errors may occur:Sensitizations in the absence of corresponding symptoms are misinterpreted as an allergy.Allergens absent or barely present in the extract can cause false-negative or excessively low IgE values.Laboratory errors can cause both false-negative and false-positive findings.Total IgE needs to be considered when interpreting quantitative IgE concentrations: Very high total IgE (e. g., >2000 kU/l in patients with atopic eczema) is often associated with multiple sensitizations of questionable clinical relevance.In the case of low total IgE (e. g., < 20 kU/l), low specific IgE values can also be of diagnostic relevance and the detection or exclusion of sensitization can be hampered.Conclusion: Specific IgE detection indicates IgE-mediated sensitization that is only of clinical relevance in conjunction with a corresponding patient history or positive controlled challenge.4.2.2. Cellular techniques to detect IgE-dependent sensitizationIgE-mediated sensitization can also be detected indirectly using a basophil activation test (BAT). These tests are complex, costly, and only helpful in in vitro diagnosis in individual cases of suspected food allergy (e. g., in unusually low total IgE, < 20 < 10, < 5 kU/l).The severity of a clinical reaction should be measured on the basis of the patients history and/or challenge testing rather than on quantitative test results.strong consensusValid indications for IgE determination include:allergy testingconsensusa)Justified suspicion of an IgE-mediated food allergyb)Targeted exclusion of an IgE-mediated food allergyc)A severe reaction to foodd)Justified suspicion of sensitization to food not suitable for skin testinge)Conditions that preclude skin testing or the evaluation thereof (e. g., urticaria factitia, generalized skin disease, use of drugs that impair skin testing results)f)Very young patient age (infants or young children)g)Greater diagnostic value expected from molecular allergy diagnosticsTotal IgE should be measured to support interpretation.consensusIgE diagnostics using single allergens for the detection of sensitization should be used for specific diagnostic investigations.strong consensusIn vitro diagnostics using single allergens canincrease test sensitivity particularly in the case of unstable or underrepresented food allergens.majority approvalSensitization to certain allergen components (see tables in Sect. 4.2) can be associated with systemic allergic reactions. Determining these components increases analytical specificity compared with food extracts.strong consensusKleine-Tebbe, Ballmer-Weber, Jappe, Saloga, Wagenmann4.3. Skin testingWhich skin testing method is well suited to diagnose food allergy?What should be given special attention in skin testing to diagnose food allergy?Skin tests are a central component in food allergy diagnosis. The skin prick test is the preferred skin testing method. Diagnostic sensitivity and specificity can vary according to the material used (extract, native foodstuff). The method is generally safe and results are available within 20 min.4.3.1. ContraindicationsContraindications to skin testing include:Active skin disease in the test areaUse of medications that affect test results (e. g. antihistamines)Presence of urticaria factitiaSevere anaphylactic reaction in the patient history to the foodstuff to be investigated (relative contraindication)4.3.2. Restrictions in the use of commercial extracts and criteria for their useNumerous commercial food extracts are not standardized in terms of their allergen content. Skin tests have a greater diagnostic sensitivity and greater negative predictive value (NPV) but a limited PPV in children with atopic eczema and food allergy to, e.g., milk, egg, or peanut. Skin tests using extracts from plant foods (fruit, vegetables) often (if not always) have insufficient test sensitivity and diagnostic sensitivity. Endogenous enzymatic processes cause less stable allergenic proteins in the extract to degrade (e. g., Bet v 1-homologous food allergens). In addition, important allergenic components are sometimes present in lower concentrations. In such cases, prick-to-prick testing with fresh foodstuffs offers an alternative to commercial extracts (Tab. ​(Tab.1414).Commercial extractSuitable for native testingaLimited suitability for native testingbFoods of animal originFish++Meat(+)+Hen‘s egg++Seafood and snails++Milk++Foods of plant originPineapple+Apple+Cereals(+)+Strawberries+Peanut++Spices+Hazelnut++Carrot+Kiwi+Lychee+Mango+Oilseeds (e. g., poppy, sesame)+Peach+Celery(+)+Mustard+Soy(+)+Tomato+Grapes+Sugar snap pea+aIdeally, a control subject is tested due to irritant components (testing control subjects with non-approved test preparations is illegal in Germany according to the German Medicinal Products Act).bHigh irritant potential.cData on extract quality is available only for individual foods; hence this table can only provide limited information. As a basic principle, testing with native foods generally has better diagnostic sensitivity at lower specificity.In practice, skin testing with pollen extracts is helpful in the case of suspected pollen-associated food allergy. Commercial solutions can be used for those foods that have been shown in studies to have high test sensitivity and diagnostic sensitivity in food allergy diagnosis, such as fish extract. In the case of fruit, vegetables and meat, prick-to-prick testing using native foodstuffs is considered more sensitive. Therefore these are more diagnostically sensitive, however less specific.4.3.3. Advantages and disadvantages of testing with native materialSkin testing with native material can be helpful if original recipes are tested. A skin test, e. g., with a cooked, mixed original recipe, allows to assess whether the possible individual components should be investigated. Furthermore, skin testing offers to test the processed foodstuffs in a given meal and to assess any possible alterations to their allergenicity.One drawback of skin testing with native material is in its lower diagnostic specificity. Thus, one may obtain e. g. false-positive results due to the irritant potential of native foodstuffs. In rare cases, native foodstuffs used for skin testing can cause systemic allergic reactions. Moreover, this test principle is not standardized.4.3.4. Other skin testing methods and their diagnostic valueIntracutaneous tests using foods are not relevant in practice, since they bear a considerably higher risk of systemic reactions and may lead to false-positive reactions. Atopy patch tests using fresh foods, e. g., based on the suspicion that atopic eczema may be aggravated by food allergens, only rarely yield helpful additional information.Greater emphasis will be placed on the use of fresh foods in skin testing in the future, since the number of commercially available extracts declines as these today need to be approved as medicinal products according to European legislation. Due to the high costs associated with this procedure manufacturers will only offer the most demanded allergen sources [2, 3, 44].The skin prick test is the preferred skin testing method in the diagnostic work up of IgE-mediated food allergy.strong consensusScratch tests, rubbing tests, intracutaneous tests and closed epicutaneous tests (atopy patch test) are not recommended for the routine diagnosis of food allergy.consensusTests should be conducted using commercially available test solutions or native foodstuffs, depending on the stability and safety of the food allergens.strong consensusZuberbier, Szépfalusi4.4. Diagnostic elimination diet and challenge testingWhat is a diagnostic elimination diet and for how long should it be performed?How important is food allergen challenge testing and how should it be performed?4.4.1. Elimination dietsA diagnostic elimination diet comprises the controlled avoidance of foods for a certain period of time. In cases of chronic disease such as atopic dermatitis, the diet should not last longer than 1 to maximally 2 weeks, except in exceptional cases. Longer times (3–4 weeks) may be required for non-IgE-mediated reactions. There is evidence to suggest that long-term elimination in IgE-mediated food allergy increases the risk of immediate reactions upon reintroduction of relevant foods. It should therefore be avoided. A diagnosis can be supported or excluded by evaluating detailed (complete) documentation in the form of a diet and asymptom diary. This approach avoids unnecessary food restrictions.Oral food challenge should be performed under medical supervision following a diagnostic elimination diet.The extent of dietary measures needs to be reviewed if no symptom improvement is seen under diagnostic food avoidance. In such cases, either symptoms are non-food-related or not all potential triggers have been identified and hence eliminated, or augmentation factors are affecting reactivity.4.4.1.1. Use of therapeutic infant formula during the diagnostic processNon-breastfed infants with suspected cow‘s milk allergy require a cow‘s milk substitute in the form of an extensively hydrolyzed infant formula or an amino acid-based formula during the period of diagnostic elimination; formulas should be selected on a case-by-case basis (see also Sect. 5.3). Allergy to the avoided food is highly unlikely if symptoms fail to improve despite a carefully controlled elimination diet. In such cases, the food in question should be reintroduced into the infant‘s diet in order to ensure a varied diet and to avoid unnecessary dietary restrictions.4.4.2. Oral food challengesIn general, controlled oral challenge testing is required for the diagnosis of a food allergy or to prove clinical tolerance (Tab. ​(Tab.15).15). Furthermore, it has been repeatedly shown that patient quality of life improves irrespective of the outcome of oral food challenge testing. The procedure for food challenge testing has been described in detail in national (GPA-Manual: https://www.gpau.de/fileadmin/user_upload/GPA/dateien_indiziert/Stellungnahmen/Manual_NMA_2009.pdf) and international guidelines (EAACI, PRACTALL consensus paper). The „food allergy due to immunological cross reactivity with inhalant allergens“ guideline [3] describes the particular features of challenge testing in pollen-associated food allergy in greater detail.Challenge design open vs. blinded (single- or double-blind) titrated vs. single-stepTest design should be chosen according to the indication and purpose of challenge testing.Food challenge meal preparationThe food challenge meal should contain, as realistically as possible, the usual edible form of the food that elicits the reaction. Processing a food, as well as its incorporation in a matrix, can significantly affect its allergenicity (e.g., raw vs. cooked egg). Fresh fruit and vegetables should preferably be used in challenge testing to confirm pollen-associated food allergy, since triggering proteins are generally heat-labile.Matrix selectionCareful attention should be paid to ensure that no other allergens to which the patient reacts are included in the meal. As few ingredients as possible should be used. Placebo meals should resemble the sensory characteristics of the test food as closely as possible.DosageNumber of dosesIn most cases, titration in seven semi-logarithmic steps should be selected. A single dose may be adequate if negative challenge is expected and there are no safety concernsInitial doseIn clinical routine, an initial dose of 3 mg food protein is generally appropriate for most foods. Lower doses should used for threshold dose challenges and high-risk patients.Maximum doseCorresponding to an age-adjusted portion, 3 g food protein is appropriate for most foods.Cumulative total doseA cumulative total dose should be administered the following day or on another day, since some patients react only upon repeated administration.Time interval between doses20–30 min, but should be adjusted according to previous history4.4.2.1. Decision-making criteria and influencing factorsThe recommendations include diverse variables that need to be taken into consideration in order to be able to perform challenge tests tailored to the individual patient:Patient selectionSafety aspectsType and quantity of the food to be administeredTime interval between individual administrationsAssessment criteriaObservation periodFormulationsWhen performing challenge testing with cross reactive foods of inhalative allergens or challenge testing in adults need to consider further aspects such as:Possible cumulative effects during pollen seasonAltered response due to augmentation factors (physical exercise, infection, drug use, and alcohol consumption)Comorbidities (e. g., unstable bronchial asthma, mastocytosis)4.4.2.2. Performing and interpreting oral food challengesOpen or blind food challenge tests can be performed (single- or double-blind format). Sequential mucosal and systemic challenge can be employed in the case of pollen-associated food allergy. Only a negative result represents a reliable finding in open oral challenge testing. Double-blind placebo-controlled food challenge (DBPCFC) is considered the gold standard for the diagnosis of food allergy.A negative food challenge should be confirmed by a repeated administration of the cumulative dose the following day at the earliest. The time and personnel requirements for DBPCFC are significant. Thus, a negative open challenge may represent a reasonable first step towards excluding a food allergy. DBPCFC should be preferred over open challenge in patients with moderate or severe atopic eczema. This test format should also be performed in the case of subjective, delayed or atypical symptoms or if patients (or parents) are anxious. Furthermore, it is required to use DBPCFC in scientific investigations, e. g., to establish the clinical relevance or potency of certain allergens, but also if a threshold dose for defined food allergen is determined. The food should be administered in „blinded“ form in terms of:TasteAromaTextureAdministration form (consistency, color and form)Placebo and verum should be indistinguishable from each other.In order to avoid severe reactions, patients receive the food to be tested in a titrated manner, generally in semi-logarithmic increments at time intervals of 20–30 min. Quantities between 3 mg and 3 g – based on the protein content of the administered food – have proven to be sufficient for many foodstuffs such as cow‘s milk, hen‘s egg, peanut and tree nuts.Food challenges are generally discontinued as soon as a clinically detectable reaction occurs, or are ended if the final dose administered, as well as repetitive administration of the cumulative total dose (e. g., the following day) is tolerated without clinical symptoms. If subjective symptoms occur, the subsequent dose should be exposed or the previous dose repeated. Immediate-type reactions generally occur within 2 h of the last food intake. Since atopic dermatitis may worsen several hours (or even over the course of the following day) after food challenge, it is necessary to perform a skin examination on the following day. Although urticaria and/or angioedema are the most common immediate-type reactions, gastrointestinal, respiratory and cardiovascular symptoms may occur and patients require to be medically supervised upon provocation.4.4.2.3. Safety aspectsFor reasons of safety, oral challenges should only be performed in a setting where allergic reactions, including anaphylaxis, can be treated adequately and in an age-appropriate manner. Personnel should be trained and experienced in early recognition of symptoms and emergency management. Age- and weight-appropriate emergency medication that may potentially be required should be noted, e. g., in the patient‘s file prior to the challenge test and kept ready to use. In the case of non-IgE-mediated reactions, challenges should be tailored to the individual requirements of the patient.Oral food challenge (in particular DBPCFC) is the gold standard for the diagnosis of IgE-mediated food allergies.strong consensusAugmentation factors should be taken into consideration in challenge tests. Food challenges should be performed to confirm or exclude allergy.strong consensusFood challenges built the basis to safely determine the patient‘s range of tolerated food and enables counseling on appropriate allergen avoidance and risk assessment for severe reactions (anaphylaxis).consensusA negative oral challenge should be followed-up by a repeated administration on the following day at the earliest of the tested food in a quantity adjusted to age- and everyday eating habits.strong consensusOral food challenges should be performed at specialized centers where emergency measures are available. In cases where challenge testing poses a high risk for severe allergic reactions, intensive care support should be available.strong consensusIndicationRationaleFrequent indications for oral food challenge1.Inconclusive diagnostic situation despite detailed patient history and test results (e.g., in patients with multiple food sensitizations due to sensitization to panallergens such as profilin or Bet v 1)2.Suspected allergic reaction for which the trigger remains unidentified despite allergy diagnostics (reaction following a composite meal)3.Sensitization detected, yet the relevant food has never been consumed, or only in small quantities4.to confirm clinical relevance following improvement in clinical symptoms, e. g., atopic dermatitis, during elimination diethttp://5.To detect the development of natural tolerance (in persistent IgE reactivity)http://6.To prove the efficacy of causal therapy, e.g., oral immunotherapy in the context of clinical researchstrong consensusLange, Reese, Schöfer, Niggemann, Bischoff, Beyer4.5. Alternative diagnostic testsWhich alternative diagnostic methods are available?What is the relevance of alternative diagnostic tests in confirming food allergy?Some physicians and alternative practitioners use a number of alternative diagnostic methods in the case of suspected food-related symptoms. These can be subdivided into two categories:Tests based on dubious theoretical foundations, lacking validity and reproducibility. They include bioresonance, electroacupunture, hair analysis, iridology, kinesiology, and cytotoxic food testing (ALCAT test). These methods have not been successfully validated either technically or clinically to justify their use.Tests that yield the measurement of data but resulting in a false interpretation: Immunoglobulin G (IgG) or IgG4 antibody determination and lymphocyte transformation tests with foods do not enable to distinguish between affected and healthy individuals [45] neither in food allergy or in food intolerance. Their lack of diagnostic specificity results frequently to positive findings in healthy individuals. Food-specific IgG or IgG4 merely indicates that an individual had repeated contact with the according food and represents a physiological immune response to a foreign protein. Lymphocyte proliferation following food stimulation and serum IgG or IgG4 to food can be elevated in allergy sufferers. However, these tests are not suited for an individual diagnosis of food hypersensitivity due to their variance and poor specificity [46, 47, 48, 49, 50, 51, 52, 53].The EAACI [52], the American Academy of Allergy, Asthma & Immunology (AAAAI), and the Canadian Society of Allergy and Clinical Immunology (CSACI) advise against testing for IgG/IgG4 against foods in suspected food allergy or intolerance.Other diagnostic test methods (e. g., bioresonance, electroacupunture, kinesiology, cytotoxic food tests (ALCAL test), as well as IgG/IgG4 determinations and lymphocyte transformation tests with foods, should not be used to diagnose food allergy or intolerance.strong consensusNiggemann, Kleine-Tebbe, MahlerGo to:5. Course and treatment of food allergy5.1. Natural courseCan food allergy develop into to tolerance?To which food allergens are likely/unlikely to develop into tolerance?Most primary IgE-mediated food allergies take the following course:Onset in infancy or early childhood and spontaneous remission either by school age or adolescence [26] depending on the food and comorbidities [54]/cofactors.Although rare, later onset at school age or adulthood is possible.The natural course depends on the food source: cow‘s milk [55], hen‘s egg [56, 57], wheat [58], and soy allergies [59] tend to develop into spontaneous remission during the first years of life. Peanut [60, 61, 62, 63, 64], tree nut [65], but also fish and crab allergies [66], often persist. High specific IgE titers frequently correlate with clinical relevance and are less likely to develop into clinical tolerance. Specific IgE antibodies to food are often found as early on as in infancy and early childhood. Values can rise or fall later on. A decrease may be associated with tolerance development. There is evidence to suggest that the natural course of food allergy alters, resulting in slower tolerance development [25, 54, 67]. Recent data, primarily from the US, indicate that low specific IgE antibodies, low skin prick test diameter and mild atopic eczema tend to be associated more frequently with food allergy remission [25].Food allergies in adulthood can represent either a persistent childhood form or a de novo sensitisation. Major triggers of food allergy in adulthood according to frequency are apple, peanut, kiwi, hazelnut, peach, cow‘s milk, hen‘s egg, wheat, fish, and shrimp [68]. Cross reactivity due to specific IgE to inhalant allergens are more frequent compared with primary food allergies – particularly in the form of birch pollen-associated food allergies in German-speaking countries (see Sect. 4.2). These adult-onset food allergies may persist [69].Due to the natural course of cow‘s milk, hen‘s egg, wheat and soy allergy in children, oral food challenges should be repeated at regular inter-vals (e.g., every 6, 12 or 24 months) to assess for tolerance development.strong consensusProvocation testing should be performed at longer intervals (e.g., every 5 years) in children with peanut and primary tree nut allergy, as well as fish and oilseed allergy.consensusSzépfalusi, Lepp, Lange5.2. Treatment5.2.1. Acute treatment of food allergyWhat are the treatment forms available for food allergy?When and how are they applied?5.2.1.1. Core questionsHow effective are pharmacological and non-pharmacological interventions in the treatment of acute, non-life-threatening reactions in food allergy?How effective are pharmacological and non-pharmacological interventions in the long-term care of food-allergic patients?5.2.1.2. Treatment of IgE-mediated food allergiesFood allergy treatment is based on:a) Short-term management of acute reactionsb) Long-term strategies to reduce the risk of further reactionsThe latter include dietary treatment and training programs. Training programs are designed to help affected individuals to avoid allergens and to learn how to react upon accidental allergen contact (e. g., use of emergency medicine). Sublingual or oral immunotherapy appear to offer new perspectives to achieve clinical tolerance.5.2.1.3. Treatment of acute reactionsAssessing the risk of potentially severe reactions is an essential part of successfully caring for food allergy patients. This risk varies according to subgroup. Thus, patients withprevious anaphylactic reactions,severe and/or uncontrolled bronchial asthmaorspecific underlying diseases (mastocytosis)are at greater risk.The „Anaphylaxis“ guidelines describe how to recognize and to treat anaphylactic reactions. In addition to emergency medical measures (e. g., administering fluids and oxygen, monitoring circulation, ABCD measures), emergency medication should be administered immediately. These are defined as immediate-action first-aid medications aimed at preventing the pathophysiological effects of anaphylaxis. They include adrenaline, bronchodilators, antihistamines and glucocorticosteroids [70]. Intramuscular administration of adrenaline is the first-line treatment in anaphylaxis [20].A systematic overview of EAACI guidelines on the treatment of food allergies revealed only weak evidence for the efficacy of H1 antihistamines. This finding relates to three randomized and two non-randomized comparative studies in children and adults with acute non-life-threatening symptoms caused by food allergy [71].There is no evidence to suggest that antihistamines are effective against respiratory or cardiovascular symptoms. However, the prophylactic use of antihistamines can mask early symptoms of anaphylaxis, thereby delaying the requisite use of adrenaline [70].According to the guideline on the acute treatment of anaphylaxis [70], glucocorticosteroids also belong, alongside adrenaline and antihistamines, to the arsenal of acute treatments for food-related allergies, although there are no systematic clinical studies on this indication [72, 73, 74]. A nonspecific membrane-stabilizing effect following high-dose administration (500–1000 mg methylprednisolone) has been postulated in reviews. However, they are also effective at intermediate doses (1–2 mg/kg methylprednisolone) in the treatment of asthma and act against prolonged or biphasic reactions. All medical practice should have acute medication available.5.2.2. (Long-term) Drug treatment of food allergyStudies on the prophylactic use of mast cell stabilizers have yielded varying clinical results [77]. Four randomized studies and two non-randomized comparative studies showed that mast cell stabilizers are able to reduce symptoms, while three randomized studies found no effect. Thus, it is currently not possible to make a standard recommendation on the use of mast cell stabilizers; instead, a differentiated approach depending on the patient cohort investigated is required.The mode of action of mast cell stabilizers, such as cromoglicic acid or ketotifen, is not yet understood. While reduced disease activity has been described in intestinal symptoms due to its potentially positive effects on the intestinal barrier, there are negative reports on the efficacy of cromoglycate acid in the skin and extraintestinal manifestations.At present, there are no randomized treatment studies on budesonide in IgE-mediated food allergy. Existing recommendations are based on case and expert reports, and the extrapolation of data to patients with eosinophilic disease of which 50 % are associated with IgE-mediated allergy [85, 86, 87].The above-mentioned treatment options using mast cell stabilizers and budesonide can be considered on an individual basis in the case of gastrointestinal symptoms alone. They should be critically reviewed, primarily by gastroenterologists, in terms of their efficacy.Acute treatmentPatients at risk of severe reactions should be equipped with emergency medication, including an adrenaline autoinjectorstrong consensusSevere allergic reactions to food should be treated with intramuscularly administered adrenaline.strong consensusAntihistamines can be used in acute non-life-threatening symptoms, most notably to treat urticarial and mucosal reactions.strong consensusThe prophylactic use of antihistamines is not be recommended.consensusLong-term treatmentSince cromoglycate acid and ketotifen exhibited no treatment effect when all patient cohorts were taken into consideration, it is currently not possible to make a standard treatment recommendation for all patient groups. Gastrointestinal symptoms require individual treatment decision-making and monitoring.consensusLepp, Huttegger, Raithel, Werfel, Schreiber5.3. Long-term management of food allergyHow does one implement avoidance measures in everyday life?5.3.1. Dietary treatment and allergen labelingLong-term food allergy management includes:Avoidance of relevant foodsSubstitution with suitable foodsThe implementation of treatment measures in everyday life [4].Avoidance is the most important intervention to prevent the onset of symptoms. Since, for ethical reasons, randomized controlled studies in non-food-allergic individuals, or in food-allergic individuals from whom dietary treatment is withheld in the control group, are critically viewed, valid data on the efficiency of avoidance measures are not available.However, this lack of consistent data on the efficacy of avoidance [88, 89, 90, 91] can not be interpreted as evidence that elimination diets are ineffective.Therapeutic elimination diets are tailored to the individual allergy and nutritional requirements of the affected individual. The requirements, aims, and expected results of dietary therapy vary considerably according to age and elicitating or causing allergen profile (primary vs. secondary food allergy).Ideally, affected individuals receive treatment advice from a dietician with allergological experience. Individual tolerance to the eliciting food can vary between allergic individuals and may change on an individual basis. This applies to primary but also secondary food allergies. For dietary therapy it is important to take into consideration the augmentation factors for allergic reactions discussed in Sect. 4.1, „Patient history and diet/symptom protocols.“Lifetime prevalence (self-reported; 95 % CI) [16]Lifetime prevalence (oral food challenge-proven; 95 % CI[16]Spontaneous remission (up to the age of)ReferenceCow‘s milk6.0 % (5.7–6.4)0.6 % (0.5–0.8)80 % (5 years)[55]Hen‘s egg2.5 % (2.3–2.7)0.2 % (0.2–0.3)66 % (7 years)[56, 57]Wheat3.6 % (3.0–4.2)0.1 % (0.01–0.2)29 % (4 years)56 % (8 years)65 % (12 years)[58]Soy-0.3 % (0.1–0.4)25 % (4 years)45 % (6 years)69 % (10 years)[59]Peanut0.4 % (0.3–0.6)0.2 % (0.2–0.3)0 % [63] to 57 % [64][60, 61]Fish2.2 % (1.8–2.5)0.1 % (0.02–0.2%)0 %[66]Crustaceans1.3 % (0.9–1.7)0.1 % (0.06–0.3)0 %[66]CI, confidence interval5.3.2. Cow‘s milk substitutionCow‘s milk allergy with the onset before the age of 1 year requires special dietary treatment (extensively hydrolyzed amino acid-based formula) in order to ensure that infants grow and thrive in an age-appropriate manner. However, in such cases, the only means of providing an infant with sufficient nutrients is mainly via bottle-feeding.The specific formula to be used is selected on a case-by-case basis: An extensive hydrolysate is generally the formula of first choice. Amino acid-based formulas can be beneficial in those affected by severe (notably also gastrointestinal) symptoms [90, 92, 93, 94, 95].Soy formulas are not be recommended in infants aged under 12 months. Moreover, feeding with soy products in the first year of life is viewed critically due to their possible phytoestrogen, phytate and aluminum content. This is particularly relevant in the case of high intake per kilogram bodyweight, i. e., up to the age of 6 months. The risk:benefit ratio of soy formula in a predominantly milk substitute-based diet with low quantities of other foods is unfavorable.Like sheep and goat milk, partially hydrolyzed infant formulas are not well suited for the treatment of cow‘s milk allergy [97, 98].5.3.3. Food avoidance during breastfeedingIf a breastfed infant is affected by symptoms caused by the mother‘s intake of certain foodstuffs, the breastfeeding mother should eliminate the suspected triggering food(s) from her diet followed by dietary counseling. Mothers should receive dietary advice if milk and milk products need to be eliminated on a long-term basis. Supplements are required in cases where it is not possible to achieve sufficient intake, e. g. calcium.5.3.4. Monitoring and re-evaluating clinical relevanceExtensive and long-term avoidance measures need to be monitored carefully. They may cause:Insufficient nutritional intakeImpaired quality of lifeThus, counseling on dietary intake should include the calculation and possibly optimization of nutritional values to ensure a balanced and age-appropriate diet.In order to ensure that avoidance measures are not maintained for longer than necessary, it is important to regularly review their clinical relevance. Cow‘s milk or hen‘s egg allergy should be re-evaluated by means of challenge testing at 6- to 12-month intervals in young children and 12- to 18-month intervals in older children.The re-evaluation of prognostically unfavorable allergies, e. g. caused by nuts or peanuts, should be made on a case-by-case basis. Primarily such cases should be considered where no accidental allergic reactions have occurred. A follow-up patient history should be taken in case of pollen-associated food allergies to compile an accurate record of clinically relevant cross reactions over time.5.3.5. Patient instruction and allergen labelingPatient training is considered a key instrument of dietary intervention to achieve long-term elimination in everyday life.Training programs are designed to teach patients, their families, relatives and caregiversto be aware of and to identify risk situationsto be able to read lists of ingredientsto completely avoid relevant triggers (in and outside the home (e. g., in restaurants))Patients should be informed about the European Food Information Regulation (EU FIR):1. The EU FIR requires that the 14 most important triggers of allergies and non-allergic intolerance need to be declared if they, or their associated products, have been included as an ingredient in a food (i. e., knowingly and as part of a recipe). These are the following:Gluten-containing cereal: wheat (spelt, khorasan wheat), rye, barley, oatsCrustaceans, egg, fish, peanuts, soybeans, milkNuts: almonds, hazelnuts, walnuts, cashew nuts, pistachio nuts, pecan nuts, Brazil nuts, macadamia (Queensland) nutsCelery, mustard, sesame seeds, lupine, and molluskssulfitesMandatory labeling applies to pre-packaged as well as non-pre-packaged foods.2. There is no legal framework governing the labeling of allergens that occur unintentionally in packaged or loose products. Trace allergen labeling, which is voluntary, is not able to provide information at the level (allergen amount) of contamination or its true likelihood due to the lack of limit values, nor does its absence signify per se that a food is safe. Thus, it should always be interpreted on an individual basis.Patients, their families, relatives and caregivers should be given the following informations:Substitute productsRecipes to prepare their usual and preferred meals despite avoidance5.3.6. Therapeutic use of pro- and prebioticsDue to a lack of data the use of pre- and probiotics in the treatment of food allergy is not recommended.An appropriate elimination diet is the keystone of food allergy management.strong consensusAn elimination diet should be based on sound allergy diagnostic methods. Regular reviews regarding the indication are reqiuired.strong consensusFood-allergic individuals that adhere to long-term dietary elimination should receive advice from dieticians with proven allergological expertise.strong consensusPatients should be informed about allergen labeling (in accordance with the FIR), as well as the current gaps therein.consensusExtensive hydrolysate or, alternatively, amino acid-based formulas are recommended in cow‘s milk allergy, particularly in infants and, where appropriate, young children.strong consensusSoy-based formulas are the milk-substitute products of second choice in cow‘s milk allergy and are not recommended for infants below 12 months.strong consensus5.3.7. Gaps and important areas of research with regard to long-term managementLong-term effect of elimination diets on nutrition and quality of lifeEffect of altered allergens (cooked milk/egg) on tolerance developmentLong-term drawbacks of rice- and soy-based formulas in terms of a balanced dietStrain-specific (relating to certain micro-organisms) effects on food allergy management using probioticsDetermination of allergen-specific threshold values. Objective: To protect food-allergic individuals from severe reactions and to optimize food labeling in terms of ingredient and trace allergen labeling (unintended cross contact).5.4. Immunotherapy in food allergyIs it possible to perform effective immunotherapy in food-allergy patients?5.4.1. The use of allergen-specific immunotherapy (AIT) in food allergyNumerous attempts have been made to treat primary food allergy with:subcutaneous (SCIT),sublingual (SLIT) ororal (OIT) allergen-specific immunotherapyusing foods or food extracts.Primary sensitizing pollen extracts have been used sublingually and subcutaneously to treat pollen-associated food allergy; in addition, oral and sublingual application of the food has also been investigated.5.4.2. The use of SCIT in food allergyTwo studies showed evidence that treatment with verum is superior compared with placebo in SCIT using food allergen extracts for primary food allergy [100, 101]. Four other studies made similar observations on the efficacy of subcutaneously applied pollen allergens on pollen-associated food allergy [102, 103, 104, 105]. These studies investigated the effect of SCIT on birch-associated apple/hazelnut allergy. A randomized study found no effect for birch SCIT on birch-associated hazelnut allergy [106].5.4.3. The use of SLIT in food allergySLIT with food allergens, as investigated in four randomized studies, improved tolerance and reduced allergic symptoms to peanut, hazelnut, and peach [107, 108, 109, 110]. No improvement was seen in apple-allergic subjects in a randomized study using birch-pollen allergens [111].5.4.4. The use of OIT in food allergyOIT using a wide variety of food allergens improved clinical tolerance in children and adults. This was shown in a number of randomized and non-randomized controlled studies – primarily with cow‘s milk, hen‘s egg, and peanut [112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128] – as well as in systematic reviews based partially on these studies [129, 130, 131, 132, 133]. However, (mostly mild but in rare case also severe) side effects were observed in many patients undergoing OIT with allergens.A randomized study showed OIT with cow‘s milk or hen‘s egg to be not more effective than elimination dieting in terms of tolerance development; however, these studies were conducted in young children [134]. Although a further study showed OIT to be more effective in cow‘s milk allergy when compared directly with SLIT, it also caused more side effects [116]. One study showed that the regular consumption of apples in birch-associated food allergy resulted in tolerance [135].While results for OIT appear to be promising the evidence is overall poor. Thus, OIT should be used only in controlled clinical studies [77]. There are no data on long-term effects yet. Due to conflicting data on efficacy, subcutaneous and sublingual immunotherapy with pollen allergens should only be used in pollen-associated food allergy provided the primary inhalation allergy also requires treatment [3].Primary food allergyAt present, specific oral, sublingual, or subcutaneous immunotherapy with food allergens should only be used in primary food allergy in the context of controlled studies.strong consensusPollen-associated food allergyPollen-associated food allergy should only be treated with subcutaneous or sublingual immunotherapy using pollen allergens in the case of concomitant pollen-related respiratory symptoms.strong consensusAt present, oral immunotherapy with food allergens should only be used in pollen-associated food allergy in the context of controlled studies.strong consensus5.5. Everyday management of patients at risk of anaphylaxisHow can food-allergic patients deal with their disease successfully in everyday life?5.5.1. Patient information and risk assessmentPatient information and training are the main tasks of food allergy management in everyday life. Risk assessment is essential in patients at increased risk of severe allergic reactions.Patients, relatives and caregivers receive:A patient tailored management plan (see Sect. 5.3.1.)An anaphylaxis identification cardAn anaphylaxis emergency plan (see anaphylaxis guidelines [70].5.5.2. Emergency planThe emergency plan should take into consideration all the possible variables that could impact the identification and treatment of allergic reactions to food, including:Patient agePatient/family education levelType and extent of the food allergyComorbiditiesPlace of residence and access to medical assistanceThe procedure management and in particular what should be done in the case of specific symptoms, should be easy to understand to a non-informed third party.5.5.3. Instruction and anaphylaxis trainingTraining should include the following aspects:Patient-specific avoidance strategies at home and in their social environmentRecognizing and interpreting warning signalsWhen and how allergic reactions need to be treatedWhen and how to use an adrenaline autoinjector5.5.4. Who requires instruction?Individuals professionally confronted with anaphylaxis patients should be considered in instruction programs. These include:general practitioners and pediatriciansdieticianskitchen personnelteachers and caregiversfirst aiders in companiesTogether, a multidisciplinary approach and the availability of written or online information on food allergies clearly improve knowledge and promote the correct use of adrenaline autoinjectors, thereby contributing to the reduction of allergic reactions [136].In addition to direct family members other persons with whom the allergy sufferer comes into close contact in their social environment should also be informed e. g., childcare center, school or workplace, flight personnel etc..5.5.5. Patient organizationsReferring patients to relevant patient organizations, such as the German Allergy and Asthma Association (Deutsche Allergie- und Asthmabund, DAAB; www.daab.de) for questions regarding everyday management is helpful. A standardized training program („AGATE,“ Arbeitsgemeinschaft Anaphylaxie – Training und Edukation, „German working group on anaphylaxis training and education“; www.anaphylaxieschulung.de) is available in Germany for severe allergic reactions (anaphylaxis).Patients, their relatives and caregivers should be informed about the foods to be avoided and practical information on avoidance measures, the recognition and self-management of future reactions should be givestrong consensusThe option to contact a patient organization should be communicated to patients.consensusFood-allergic patients at risk of anaphylaxis should receive an anaphylaxis identification card and should participate in patient/parent training.strong consensusSchnadt, Fischer, SchöferGo to:6. Current developments in the diagnosis and treatment of food allergiesWhat new diagnostic and therapeutic methods are currently under development?6.1. Diagnostic methodsMolecular (synonym: component-based) diagnostic tests can determine specific IgE antibodies to single food allergens. This approach improves both the test sensitivity and the diagnostic sensitivity of in vitro tests, their analytical specificity, and (in a small number of food analyses) also their diagnostic specificity:Determining specific IgE to the major allergen Ara h 2 in peanut allergy increases diagnostic specificity to between 72% and 96% [137, 138, 139, 140].An Ara h 2 greater than 40 kU/l yields a 95 % likelihood of a positive oral challenge in children with peanut allergy.ω-5-Gliadin-specific IgE is of high diagnostic relevance in exercise-induced food allergy to wheat [141].Specific IgE to rGly m 4 in soy milk allergy in birch pollen-sensitized patients considerably increases test sensitivity (lower LoQ) and diagnostic sensitivity compared with extract-based diagnostic methods.Reagents for molecular diagnostic methods are available for certain fruits (apple, peach, and kiwi), hazelnut and peanut, soy, fish, and molluscs to detect specific sensitization profiles. Further studies are needed to confirm the clinical usefulness of molecular-based IgE diagnostics. At present, whilst the determination of IgE to single allergens can contribute to risk assessment, it can not substitute placebo-controlled challenge testing.Small clinical studies have investigated basophil activation assays for the diagnosis of cow‘s milk, hen‘s egg, and peanut allergy [140, 142, 143] and for the diagnosis of pollen-associated food allergy [144, 145, 146]. The basophil activation test (BAT), which generally shows exceptional analytical sensitivity, has greater diagnostic specificity and a better negative predictive value compared with skin testing and specific IgE without influencing the diagnostic sensitivity or the positive predictive value. Since the BAT requires a special laboratory setting and since large clinical studies on diagnostic sensitivity and specificity in the area of food allergy are lacking, this test is and will continue to be recommended primarily for research in food allergy.Novel diagnostic options are emerging with the determination of specific IgE against overlapping synthetic linear peptides. Although this approach has been described to date for milk [147, 148, 149], peanut [150, 151], egg [152], shrimp [153, 154], and celery [155], there are currently no peptide-based tests available on the market that can currently be recommended for routine practice.6.2. TreatmentSpecific immunotherapy approved for the treatment of food allergy is currently not available (see Sect. 5.3.2). Independent of oral and sublingual immunotherapeutic approaches [156], the efficacy and tolerability of epicutaneous allergen immunotherapy in peanut allergy is currently being investigated in a multicenter study [157, 158].Food allergies are generally IgE mediated and attempts were performed to establish anti-IgE therapy to prevent the onset of symptoms. Despite promising results [159], this approach has not pursued further for the time being. Recently a combined approach (anti-IgE antibodies plus OIT) was investigated in peanut-allergic patients [160] and suggested promising results. Considering such positive reports and studies in the literature, one should assess on an individual basis whether anti-IgE treatment is an option in patients with IgE-dependent severe repetitive life-threatening food allergic reactions.Worm, Ballmer-Weber, WatzlGo to:7. Food as an occupational allergenHow common is occupational allergy and what are the triggers?How is occupational allergy diagnosed and what is the impact for an individual‘s ability to work?7.1. Epidemiology and triggersIgE-sensitization to food allergens in an occupational setting can be acquired via the skin or the respiratory tract. Manifestations mainly occur in, but can also develop outside the workplace in form of [3]:(Occupational) allergic rhinopathy and/or allergic asthmaContact urticaria (CU) and/or protein contact dermatitis (PCD) (predominantly on the hands) [161, 162] (Tab. ​(Tab.1717).Inhalant symptoms to food allergens can cause occupational disease (OD) No. 4301 , while IgE-mediated skin manifestations cause OD No. 5101.Although CU and PCD to food allergens are extremely rare in the general population, their prevalence is significantly higher (1.5 %–20 %) in the food-processing industry depending on the occupation and cohort studied [161, 163, 164]. The prevalence of occupational asthmatic diseases in exposed employees ranges between 1 % and 20 % and is particularly high among bakers [165, 166, 167]. Flour allergy to wheat and rye is the most frequent cause of occupational allergic obstructive airway disease in Germany [166, 167].Food allergens from a wide variety of allergen sources have been described as triggers [161, 167, 168, 169]. Asthmatic bakers sensitized following inhalation exposure to wheat flour exhibit other allergen profiles compared with individuals to orally acquired wheat-induced food allergy [166, 167]. In how far certain food allergens are able to trigger specific allergic symptoms depending on the exposure route (oral, inhalant, or cutaneous) (Tab. ​(Tab.18)18) has not been clarified for most allergen sources until to date [166, 170].Allergen sourceAllergens relevant in food consumptionOccupational allergensOccupationSourceWheatω-5-Gliadin (Tri a 19), among others: wheat-dependent, exercise-induced anaphylaxis (WDEIA); Profilin (Tri a 12), nsLTP (Tri a 14); agglutinin isolectin 1 (Tri a 18), ω-5-gliadin (Tri a 19), γ-gliadin (Tri a 20), thioredoxin (Tri a 25), high-molecular-weight (HMW) glutenin (Tri a 26), among othersα-amylase-trypsin inhibitors (e.g., Tri a 28, Tri a 29.0101, Tri a 29.0201, Tri a 30, Tri a 15); thiol reductase (Tri a 27); thioredoxin (Tri a 25), triosephosphate isomerase, α-/β-gliadin, 1-Cys peroxiredoxin (Tri a 32), dehydrin (Tri a DH, serpin, glyceraldehyde 3-phosphate dehydrogenase (GA3PD), ω-5-gliadin (Tri a 19), nsLTP (Tri a 14); acyl-CoA oxidase, fructose-bisphosphate aldolase, serin protease inhibitor (Tri a 39), among othersBakers[166, 167, 169, 171]CowBeef: Bos d 6 and α-GALBovine dander Bos d 2 (lipocalin)Farmers[172]SoyGly m 4 (PR-10 homolog), Gly m 5 (β-conglycinin), Gly m 6 (glycinin) among othersSoy flour: high-molecular-weight allergens (Gly m 5 and 6)Bakers[173, 174]FiscGad m 1.0101Gad m 1.0102Gad m 1.0201Gad m 1.0202Sal s 1.0101Enolase, e.g.,Gad m 2.0101Sal s 2.0101AldolaseGad m 3.0101Sal s 3.0101Skin and inhalationParvalbumin, glyceraldehyde3-phosphate dehydrogenaseFish-processing industry, professional chefs[175, 176, 177]nsLTP, non-specific lipid transfer protein7.2. PreventionIt is essential to protect employees from allergen exposure and sensitization by minimizing occupational health risks [167, 178]. Extensive occupational dermatological and occupational medicine guidelines and recommendations are available. In order to optimize preventive measures, the relevant insurance should be informed even if a possible occupational disease is suspected:Dermatological report (Hautarztbericht) in the case of skin manifestationsOccupational disease notification in the case of airway symptoms7.3. Symptoms and differential diagnosisOccupational skin disorders of varying origin on the hands are common in the food-processing industry, whereby eczematous skin disorders predominate. Hand eczema can be of irritant, allergic and endogenous origin. Specific occupational and non-occupational triggers need to be investigated in the patient history and by means of patch testing [3, 163, 178].IgE-mediated contact urticaria to food allergens is to be distinguished from non-immunological contact urticaria (e.g., elicited by benzoic acid, sodium benzoate, sorbic acid, abietic acid, nicotinic acid ester, cinnamic acid, cinnaminic aldehyde, balsam of Peru) [163]. The latter generally remains restricted to the area of contact, while IgE-mediated contact urticaria may cause systemic manifestations [184]. Non-occupational forms of urticaria should be considered in the differential diagnosis [184].7.4. DiagnosticIn the case of suspected IgE-mediated allergic diseases related to the workplace, in particular work-related rhinopathy/asthma, the diagnostic process should be initiated early on, when the patient has not yet left the workplace [165].Stepwise diagnosis includes history-taking, skin prick testing (additional epicutaneous testing in PCD), specific IgE determination and challenge testing [161, 162, 167, 171, 180, 181]. In vivo and in vitro diagnosis are challenging, because the extracts for occupationally relevant food allergens are often lacking relevant allergens or are insufficiently standardized. The diagnostic sensitivity and specificity may vary considerably with the currently available occupational allergens depending on the allergen source and test solution [182, 185]. For the time being, parallel testing of skin prick test solutions from different manufacturers is recommended [182]. To detect CU and PCD against food allergens, skin prick tests should be performed with fresh material [161, 186].Skin prick tests to diagnose occupational type-1 allergies should be performed using a metal lancet if possible using double determinations. Where reproducible, wheals of even small diameters (≥ 1.5 mm) when controls are negative should be considered as positive and confirmed serologically [182]. Medically monitored allergen avoidance and re-exposure, as well as workplace-related challenge testing may be required to establish the diagnosis. The specific inhalation challenge test is considered the gold standard for many triggers of occupational allergy. However, a negative result in this test or following exposure at the workplace is not sufficient to exclude the diagnosis of occupational asthma in the presence of otherwise good evidence [165, 167, 180]. Further diagnostic measures are given in „Prevention of occupational obstructive ai

Common Mental Health Disorders: Identification and Pathways to Care.2COMMON MENTAL HEALTH DISORDERS2.1. INTRODUCTIONThis guideline is concerned with the care and treatment of people with a common mental health disorder, including depression, generalised anxiety disorder (GAD), panic disorder, phobias, social anxiety disorder, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). It makes recommendations about the delivery of effective identification, assessment and referral for treatment in primary care. The guideline will also be applicable to secondary care, and relevant (but does not make specific recommendations) for the prison service and non-NHS services such as social services, and the voluntary and independent sectors. A particular purpose of this guideline is to integrate existing NICE guidance on the identification and assessment of common mental health disorders and to provide recommendations to support the development of local care pathways for these disorders.The purpose of this introductory chapter is to provide an overview of the epidemiology and treatment of the common mental health disorders, and to highlight important issues related to identification and assessment of the disorders and the relevant local care pathways within the NHS.This guideline does not cover interventions to treat the disorders and should be used in conjunction with other relevant NICE guidelines, which give evidence of the effectiveness of interventions for the specific disorders, including drug treatments and psychological therapies:Self-harm: the Short-term Physical and Psychological Management and Secondary Prevention of Self-harm in Primary and Secondary Care (NICE, 2004c; NCCMH, 2004b).Obsessive-compulsive Disorder (NICE, 2005a; NCCMH, 2006).Post-traumatic Stress Disorder (PTSD) (NICE, 2005b; NCCMH, 2005).Antenatal and Postnatal Mental Health (NICE, 2007a; NCCMH, 2007).Depression (NICE, 2009a; NCCMH, 2010b).Depression in Adults with a Chronic Physical Health Problem (NICE, 2009b; NCCMH, 2010a).Generalised Anxiety Disorder and Panic Disorder (with or without Agoraphobia) in Adults(NICE, 2011a; NCCMH, 2011a).Self-harm: Longer-Term Management (NICE, 2011c; NCCMH, forthcoming). A NICE guideline on social anxiety disorder is expected in 2013.Go to:2.2. THE DISORDERSThis guideline covers the following common mental health disorders in adults (18 years and older):depression (including subthreshold disorders)anxiety disorders (including GAD, panic disorder, phobias, social anxiety disorder, OCD and PTSD).The guideline will also cover, where relevant, issues relating to comorbidity; however, as no separate NICE guideline addresses comorbid presentations of common mental health disorders, this will not be a key topic of the guideline. Groups not covered include adults with subthreshold mixed anxiety and depression, adults with psychotic and related disorders (including schizophrenia and bipolar disorder), people for whom drug and alcohol misuse are the primary problem, people with eating disorders, and children and people younger than 18 years old.2.2.1. Symptoms and presentationDepressionDepression refers to a wide range of mental health problems characterised by the absence of a positive affect (a loss of interest and enjoyment in ordinary things and experiences), low mood and a range of associated emotional, cognitive, physical and behavioural symptoms. Distinguishing the mood changes between clinically significant degrees of depression (for example, major depression) and those occurring ‘normally’ remains problematic and it is best to consider the symptoms of depression as occurring on a continuum of severity (Lewinsohn et al., 2000).Commonly, mood and affect in a major depressive illness are unreactive to circumstance remaining low throughout the course of each day, although for some people mood varies diurnally, with gradual improvement throughout the day only to return to a low mood on waking. In other cases a person's mood may be reactive to positive experiences and events, although these elevations in mood are not sustained with depressive feelings often quickly re-emerging (Andrews & Jenkins, 1999).Behavioural and physical symptoms typically include tearfulness, irritability, social withdrawal, an exacerbation of pre-existing pains, and pains secondary to increased muscle tension (Gerber et al., 1992). A lack of libido, fatigue and diminished activity are also common, although agitation and marked anxiety can frequently occur. Typically there is reduced sleep and lowered appetite (sometimes leading to significant weight loss), but some people sleep more than usual and have an increase in appetite. A loss of interest and enjoyment in everyday life, and feelings of guilt, worthlessness and deserved punishment are common, as are lowered self-esteem, loss of confidence, feelings of helplessness, suicidal ideation and attempts at self-harm or suicide. Cognitive changes include poor concentration and reduced attention, pessimistic and recurrently negative thoughts about oneself, one's past and the future, mental slowing and rumination (Cassano & Fava, 2002).Generalised anxiety disorderThe essential feature of GAD is excessive anxiety and worry (apprehensive expectation), occurring on more days than not for a period of at least 6 months, about a number of events or activities. The person with GAD finds it difficult to control the anxiety and worry, which is often accompanied by restlessness, being easily fatigued, having difficulty concentrating, irritability, muscle tension and disturbed sleep (Brownet al., 2001).The focus of the anxiety and worry in GAD is not confined to features of another disorder, for example having panic attacks (as in panic disorder) or being embarrassed in public (as in social anxiety disorder). Some people with GAD may become excessively apprehensive about the outcome of routine activities, in particular those associated with the health of or separation from loved ones. Some people often anticipate a catastrophic outcome from a mild physical symptom or a side effect of medication. Demoralisation is said to be a common consequence, with many individuals becoming discouraged, ashamed and unhappy about the difficulties of carrying out their normal routines. GAD is often comorbid with depression and this can make accurate diagnosis problematic (Wittchen et al., 2002).Panic disorderPeople with panic disorder report intermittent apprehension, and panic attacks (attacks of sudden short-lived anxiety) in relation to particular situations or spontaneous panic attacks, with no apparent cause. They often take action to avoid being in particular situations in order to prevent those feelings, which may develop into agoraphobia (Breier et al., 1986).The frequency and severity of panic attacks varies widely. Situational triggers for panic attacks can be external (for example, a phobic object or situation) or internal (physiological arousal). A panic attack may be unexpected (spontaneous or uncued), that is, one that an individual does not immediately associate with a situational trigger.The essential feature of agoraphobia is anxiety about being in places or situations from which escape might be difficult, embarrassing or in which help may not be available in the event of having a panic attack. This anxiety is said to typically lead to a pervasive avoidance of a variety of situations that may include: being alone outside the home or being home alone; being in a crowd of people; travelling by car or bus; being in a particular place, such as on a bridge or in a lift.Obsessive-compulsive disorderOCD is characterised by the presence of either obsessions or compulsions, but commonly both. An obsession is defined as an unwanted intrusive thought, image or urge that repeatedly enters the person's mind. Obsessions are distressing, but are acknowledged as originating in the person's mind and not imposed by an external agency. They are usually regarded by the individual as unreasonable or excessive. Common obsessions in OCD include contamination from dirt, germs, viruses, body fluids and so on, fear of harm (for example, that door locks are not safe), excessive concern with order or symmetry, obsessions with the body or physical symptoms, religious, sacrilegious or blasphemous thoughts, sexual thoughts (for example, of being a paedophile or a homosexual), an urge to hoard useless or worn out possessions, or thoughts of violence or aggression (for example, stabbing one's baby) (Lochner & Stein, 2003).Compulsions are repetitive behaviours or mental acts that the person feels driven to perform. A compulsion can either be overt and observable by others, or a covert mental act that cannot be observed. Covert compulsions are generally more difficult to resist or monitor than overt ones because they can be performed anywhere without others knowing and are easier to perform. Common compulsions include checking (for example, gas taps), cleaning, washing, repeating acts, mental compulsions (for example, repeating special words or prayers in a set manner), ordering, symmetry or exactness, hoarding/collecting and counting (Foa et al., 1995). The most frequent presentations are checking and cleaning, and these are the most easily recognised because they are on a continuum with everyday behaviour. A compulsion is not in itself pleasurable, which differentiates it from impulsive acts such as shopping or gambling, which are associated with immediate gratification.Post-traumatic stress disorderPTSD often develops in response to one or more traumatic events such as deliberate acts of interpersonal violence, severe accidents, disasters or military action. Those at risk of PTSD include survivors of war and torture, of accidents and disasters, and of violent crime (for example, physical and sexual assaults, sexual abuse, bombings and riots), refugees, women who have experienced traumatic childbirth, people diagnosed with a life-threatening illness, and members of the armed forces, police and other emergency personnel (Foa et al., 2008).The most characteristic symptoms of PTSD are re-experiencing symptoms. People with PTSD involuntarily re-experience aspects of the traumatic event in a vivid and distressing way. Symptoms include flashbacks in which the person acts or feels as if the event is recurring; nightmares; and repetitive and distressing intrusive images or other sensory impressions from the event. Reminders of the traumatic event arouse intense distress and/or physiological reactions. As a result, hypervigilance for threat, exaggerated startle responses, irritability, difficulty in concentrating, sleep problems and avoidance of trauma reminders are other core symptoms. However, people with PTSD also describe symptoms of emotional numbing. These include inability to have any feelings, feeling detached from other people, giving up previously significant activities and amnesia for significant parts of the event.Two further common mental health disorders, social anxiety disorder and specific phobias, are briefly described below. However, because no NICE guidelines currently exist for these disorders they will not be discussed in detail in the remainder of this chapter.Social anxiety disorderSocial anxiety disorder, also referred to as social phobia, is characterised by an intense fear in social situations that results in considerable distress and in turn impacts on a person's ability to function effectively in aspects of their daily life. Central to the disorder is a fear of being judged by others and of being embarrassed or humiliated. This leads to the avoidance of a number of social situations and often impacts significantly on educational and vocational performance. The fears can be triggered by the actual or imagined scrutiny from others. The disorder often begins in early adolescence, and although an individual may recognise the problem as outside of normal experience, many do not seek help (Liebowitz et al., 1985).Social anxiety disorder is characterised by a range of physical symptoms including excessive blushing, sweating, trembling, palpitations and nausea. Panic attacks are common, as is the development of depressive symptoms as the problem becomes chronic. Alcohol or drug misuse can develop because people use these substances in an attempt to cope with the disturbing and disabling symptoms. It is also often comorbid with other disorders such as depression (Kessler et al., 1999).Specific phobiasA specific phobia is an unwarranted, extreme and persistent fear of a specific object or situation that is out of proportion to the actual danger or threat (Humphris et al., 1995). The fear and anxiety occur immediately upon encountering the feared object or situation and tend to lead to avoidance or extreme discomfort. The person with a specific phobia recognises that the fear is excessive, unwarranted or out of proportion to the actual risk. Specific phobias result in significant interference with the activities of daily life; they are usually grouped under a number of subtypes including animal, natural environment, blood-injection-injury and situational.2.2.2. Incidence and prevalenceEstimates of the prevalence of common mental health disorders vary considerably depending on where and when surveys are carried out, and the period over which prevalence is measured.The 2007 Office for National Statistics (ONS) household survey of adult psychiatric morbidity in England found that 16.2% of adults aged 16 to 64 years met the diagnostic criteria for at least one disorder in the week prior to interview (McManus et al., 2009). In the three ONS surveys carried out so far, the proportion of adults meeting the criteria for at least one disorder increased between 1993 and 2000 but did not change between 2000 and 2007 (15.5% in 1993, 17.5% in 2000 and 17.6% in 2007). The largest increase in the rate of disorders found between 1993 and 2007 was in women aged 45 to 64 years, among whom the rate went up by about one fifth (McManus et al., 2009).More than half of the adults identified with a common mental health disorder in the ONS survey presented with a mixed anxiety and depressive disorder (9% in the past week). The 1-week prevalence for the other common mental health disorders were 4.4% for GAD, 2.3% for a depressive episode, 1.4% for phobia, 1.1% for OCD and 1.1% for panic disorder (McManus et al., 2009).In the US, Kessler and colleagues conducted the National Comorbidity Survey, a representative household interview survey of 9,282 adults aged 18 years and over, to estimate the lifetime (Kessler et al., 2005a) and 12-month (Kessler et al., 2005b) prevalence rates of mental disorders classified using theDiagnostic and Statistical Manual of Mental Disorders (4th text-revision version; DSM-IV-TR) of the American Psychiatric Association (APA, 2000). A summary of their findings can be seen in Table 1. Of the 12-month cases in the US National Comorbidity Survey, 22.3% were classified as serious, 37.3% as moderate and 40.4% as mild. Fifty-five per cent carried only a single diagnosis, 22% two diagnoses and 23% three or more diagnoses. Latent class analysis identified three highly comorbid classes representing 7% of the population, and the authors concluded that, although mental disorders are widespread, serious cases are concentrated among a relatively small proportion of people with high comorbidity (Kessler et al., 2005b).Table 1Summary of prevalence rates for common mental health disorders.In summary, at any given time common mental health disorders can be found in around one in six people in the community, and around half of these have significant symptoms that would warrant intervention from healthcare professionals. Most have non-specific mixed anxiety and depressive symptoms, but a proportion have more specific depressive disorder or anxiety disorders including panic disorder, phobias, OCD or PTSD.The location, time and duration of the survey are not the only factors to influence prevalence rates. A number of demographic and socioeconomic factors are associated with a higher risk of disorders, including gender, age, marital status, ethnicity and socioeconomic deprivation. These will be discussed below.GenderDepression and anxiety disorders tend to have a higher prevalence in women. Prevalence rates of depression have consistently been found to be between 1.5 and 2.5 times higher in women than men (Waraich et al., 2004). In the ONS survey (McManus et al., 2009) women were more likely than men to have a disorder (19.7 and 12.5%, respectively), with rates significantly higher for women across all categories of disorder except for panic disorder and OCD. The greatest difference between genders was among South Asian adults where the age-standardised rate among women (34.3% of South Asian women) was three times that of men (10.3% of South Asian men). Reasons cited in the 2007 ONS survey (McManus et al., 2009) include the impact of having children (Bebbington et al., 1991), exposure to domestic or sexual violence (Patel et al., 2006), adverse experiences in childhood and women's relative poverty (Patel et al., 1999; Piccinelli & Wilkinson, 2000).AgeIn the 2007 ONS survey (McManus et al., 2009) rates varied by age, with those aged 75 years and over least likely to have a disorder (6.3% of men and 12.2% of women). In women, the rate peaked among 45- to 54-year-olds of whom 25% met the criteria for at least one disorder. Among men, the rate was highest in 25- to 54-year-olds (14.6% of 25- to 34-year-olds, 15.0% of 35- to 44-year-olds and 14.5% of 45- to 54-year-olds).Marital statusWomen across all marital-status categories were more likely than their male counterparts to have disorders in the 2007 ONS survey (McManus et al., 2009), except for divorced people in whom the prevalence for men and women was very similar (26.6% for women and 27.7% for men). Among men, those currently divorced had the greatest likelihood of having a disorder, but variation by other marital status categories was less pronounced. For women the rate of disorder was high for divorced women, but even higher for separated women (33.0%). Men and women who were married or widowed had the lowest observed rates of disorder (10.1% of married men and 16.3% of married women; 10.4% widowed men and 17.4% widowed women).EthnicityIn the 2007 ONS survey (McManus et al., 2009), after age-standardisation of the data, there was little variation between white, black and South Asian men in the rates of any disorder. However, among women rates of all disorders (except phobias) were higher in the South Asian group. The number of South Asian women in the sample was small, so while the differences were pronounced they were only significant for disorders as a whole for GAD and panic disorder.Socioeconomic factorsIn the 2007 ONS survey (McManus et al., 2009), people living in households with the lowest levels of income were more likely to have a disorder than those living in the highest income households. A number of socioeconomic factors significantly affected prevalence rates in the 2000 ONS survey (Singleton et al., 2001): those with a depressive episode were more likely than those without a disorder to be unemployed, to belong to social classes 4 and below, to have no formal educational qualifications, to live in Local Authority or Housing Association accommodation, to have moved three or more times in the last 2 years and to live in an urban environment.An illustration of the social origins of depression can be found in a general practice survey in which 7.2% (ranging 2.4 to 13.7%, depending upon the practice) of consecutive attendees had a depressive disorder. Neighbourhood social deprivation accounted for 48.3% of the variance among practices. Other variables were the proportion of the population having no or only one car and neighbourhood unemployment (Ostleret al., 2001). The evidence therefore overwhelmingly supports the view that the prevalence of common mental health disorders, however it is defined, varies according to gender and social and economic factors.Learning disabilitiesThe rates of common mental health disorders in adults with learning disabilities are generally considered to be higher, but limited data and methodological problems (Smiley, 2005) mean that precise estimates are often not available and so uncertainty remains. In contrast, there is clearer evidence that other mental disorders such as problem behaviour have a higher rate of learning disabilities (Cooper et al., 2007). Rates of mental disorders may vary with the severity of the learning disability, being higher in more severe disability (Whitaker & Read, 2006), and challenges in assessment and diagnosis are considerable especially for those with more severe learning disabilities (Smiley, 2005; Whitaker & Read, 2006). However, some indication of the possible differential incidence of common mental health disorders can be obtained from the following studies. Richards and colleagues (2001) report a four-fold increase in the rates of affective disorders for people with mild learning disability. Rates of problems may also vary with the disorder; for example, Collacott (1999) reports a higher rate of depression in adults with Down's syndrome than in adults with other causes of learning disability. With regard to anxiety disorders, Cooper (1997) reports a rate of 2.5% for OCD in adults with a learning disability, which is higher than in the general adult population.2.2.3. AetiologyThe aetiology of common mental health disorders is multi-factorial and involves psychological, social and biological factors. Many of the common mental health disorders have similar aetiologies. For example,King and colleagues (2008) identified five immutable risk factors for depression. These were younger age, female gender, lower educational achievement, previous history of depression and family history of depression. Brewin and colleagues (2000) and Ozer and colleagues (2003) identified similar risk factors for PTSD, including a previous personal or family history of anxiety disorders or affective disorders, neuroticism, lower intelligence, female gender and a history of previous trauma. The ONS survey (McManus et al., 2009) identified factors that may be associated with increased duration of an episode of depression or anxiety. These can be broadly defined as biological factors, social stresses and life events. These risk factors will now be discussed in general. For information regarding factors for specific disorders, please refer to the relevant NICE guideline (see Section 2.1).There is good evidence for biological factors in the development of many psychological disorders. Biological factors can be biochemical, endocrine and neurophysiological (Goodwin, 2000; Malhi et al., 2005) or genetic (Kendler & Prescott, 1999), and can interact with early trauma ultimately leading to psychological distress (Heim & Nemeroff, 2001).Support for this claim often comes from family-history studies (Angst et al., 2003). A family history of depressive illness has been linked with an increased chance of developing depression (Kendler et al., 2001). Similarly, the risk of GAD in first-degree relatives of patients with GAD was five times that of controls (Noyes et al., 1987). Although specific genes conferring vulnerability to GAD have not yet been reliably identified, the genes involved in the transmission of GAD appear to increase susceptibility to other anxiety disorders such as panic disorder and agoraphobia as well as major depression (Hettema et al., 2001 and 2005; Kendler, 1996). There is some evidence to suggest that personality traits such as neuroticism may have a role in the development of common mental health disorders. Personality traits such as neuroticism have been identified as risk factors for both depression (Fava & Kendler, 2000) and GAD (Hettema et al., 2004). However, the specific role of neurotransmitters and other chemical mediators in the aetiology of common mental health disorders is currently unclear.According to a stress-vulnerability model (Nuechterlein & Dawson, 1984), it is not only biological factors that can trigger the development of a common mental health disorder. Social triggers may also play an important role (Harris, 2000). The ONS survey (McManus et al., 2009) identified perceived financial strain (Weich & Lewis, 1998a), work stress (Stansfeld et al., 1999), poor housing (Weich & Lewis, 1998b) and social isolation (Bruce & Hoff, 1994) as key factors that can influence the development of common mental health disorders. In the UK, an influential study found that social vulnerability factors for depression in women in Camberwell, south-east London, included: having three or more children under the age of 14 years living at home; having no paid employment outside the home; and not having a confiding relationship with another person (Brown & Harris, 1978). The importance of a confiding relationship has been further reiterated by Patten (1991) who found that a lack of such a relationship was a strong risk factor for depression.Negative life events, particularly those relating to health, can also impact on the development of depression and anxiety, although vulnerabilities will vary between individuals (Harris, 2000). The ONS survey identified poor physical health and problems with alcohol use as predictors of anxiety and depression (Salokangas & Poutanen, 1998), while King and colleagues (2008) found that current poorer physical and mental health functional status, based on the 12-Item Short Form Health Survey (SF-12) questionnaire, was linked to the development of depression. However, it is also important to note that depression may lead to secondary disability that compounds, and is difficult to distinguish from, the depression itself.Early life experiences as well as current social stressors must also be considered. A poor parent–child relationship, marital discord and divorce, neglect, and physical and sexual abuse almost certainly increase a person's vulnerability to depression in later life (Fava & Kendler, 2000) and can play a vital role in the development of GAD. Barlow (2000) reported that good parenting experiences are important in providing children with a secure base from which to explore the world. Problems in child–parent attachment have been linked to feelings of diminished personal control of potentially threatening events (Barlow, 2000), which can in turn increase susceptibility to psychological illness.However, when considering the importance of life events it is important to remember that events may not have a causal impact on the development of symptoms. Instead, they may act as a trigger among people who are biologically or psychologically predisposed to a disorder, for example OCD (Gothelf et al., 2004; Khanna et al., 1988). The authors of the ONS survey make the point that although these risk factors are associated with disorders and tend to increase the duration of episodes it is not clear whether or not they cause the onset of an episode.2.2.4. Development, course and prognosisFor many people the onset of common mental health disorders occurs in adolescence or early adult life, but the disorders can affect people at any point. Earlier onset is generally associated with poorer outcomes. Kessler and colleagues (2005a) reported an estimated median age of onset for anxiety disorders of 11 years and for mood disorders of 30 years in their US National Comorbidity sample. Half of all lifetime cases had started by 14 years and three quarters by 24 years. Many anxiety disorders also have a chronic course. This chronic course may be associated with a considerable delay in presenting to services, with consequent significant personal and social impairment. Therefore, Kessler and colleagues (2005a) concluded that interventions aimed at prevention or early treatment needed to focus on young people.DepressionThe average age of the first episode of major depression is the mid-20s and although the first episode may occur at any time, from early childhood through to old age, a substantial proportion of people have their first depressive episode in childhood or adolescence (Fava & Kendler, 2000).Although depression has been understood to be a time-limited disorder lasting on average 4 to 6 months with complete recovery afterwards, it is now clear that incomplete recovery and relapse are common. The World Health Organization (WHO) study of mental disorders in 14 centres across the world found that 50% still had a diagnosis of depression 1 year later (Simon et al., 2002) and at least 10% of patients have persistent or chronic depression (Kessler et al., 2003). At least 50% of people following their first episode of major depression will go on to have at least one more episode (Kupfer, 1991), and after the second and third episodes the risk of further relapse rises to 70 and 90%, respectively (Kupfer, 1991). Early-onset depression (at or before 20 years of age) and depression occurring in old age have a significantly increased vulnerability to relapse (Giles et al., 1989; Mitchell & Subramaniam, 2005). Thus while the outlook for a first episode is good, the outlook for recurrent episodes over the long term can be poor with many patients experiencing symptoms of depression over many years (Akiskal, 1986).Generalised anxiety disorderMost clinical studies suggest that GAD is typically a chronic condition with low rates of remission over the short and medium term. Evaluation of prognosis is complicated by the frequent comorbidity with other anxiety disorders and depression, which worsen the long-term outcome and accompanying burden of disability (Tyrer & Baldwin, 2006). In the Harvard-Brown Anxiety Research Program, which recruited patients from Boston hospitals, the mean age of onset of GAD was 21 years, although many patients had been unwell since their teens. The average duration of illness in this group was about 20 years and despite treatment the outcome over the next 3 years was relatively poor, with only one in four patients showing symptomatic remission from GAD (Yonkers et al., 1996). The proportion of patients who became free from all psychiatric symptomatology was even smaller, at about one in six. In patients who remitted from GAD, the risk of relapse over the next year was about 15% increasing to about 30% in those who achieved only partial symptomatic remission (Yonkers et al., 1996).The participants in the above study were recruited from hospital services and may not be representative of GAD in general. In a naturalistic study in the UK, Tyrer and colleagues (2004) followed up patients with anxiety and depression identified in psychiatric clinics in primary care and found that 12 years later 40% of those initially diagnosed with GAD had recovered, in the sense of no longer meeting criteria for any DSM-III psychiatric disorder. The remaining participants remained symptomatic, but only 3% still had GAD as the principal diagnosis; in the vast majority of patients, conditions such as dysthymia, major depression and agoraphobia were now more prominent. This study confirms the chronic and fluctuating symptomatic course of GAD in clinically-identified patients. It should be noted, however, that the majority of people with GAD in the community do not seek medical help for their symptoms (Wittchen & Jacobi, 2005) and the course of the illness in these circumstances is not established.Panic disorderPanic disorder comprises two main subtypes; panic disorder without agoraphobia and panic disorder with agoraphobia, with different presentations and often different courses. Panic disorder with agoraphobia (about one third of all presentations of panic disorder) is characterised by an avoidance of situations from which escape may not be possible or help not available in the event of a panic attack. Panic disorder with agoraphobia is also more common in women by a factor of approximately two to one. In contrast, panic disorder without agoraphobia is not situation-specific and symptoms may develop with no obvious or apparent cause (Weissman & Merikangas, 1986).The most common age of onset is from the mid-teens to the mid-20s; however, onset may occur at any time. Panic disorder often begins with occasional panic attacks that increase in frequency and which in time lead to a pattern of a generalised avoidance. The course of this disorder often follows a chronic pathway for many people with panic disorder, with agoraphobia likely to have an even more chronic course (Francis et al., 2007).Panic attacks commonly occur in many other disorders including specific phobias and social anxiety disorder, but they can also occur in GAD, drug or alcohol misuse, personality disorders and a number of physical disorders.Obsessive-compulsive disorderThe mean age of onset of OCD is in late adolescence for men and early 20s for women, although age of onset covers a wide range of ages. However, it may take individuals between 10 and 15 years or longer to seek professional help. There is often comorbidity with a range of disorders, especially depression (for example, Abramowitz, 2004; Abramowitz et al., 2003; Apter et al., 2003), and other anxiety disorders (for example, Biederman et al., 2004; LaSalle et al., 2004; Nestadt et al., 2003; Welkowitz et al., 2000).OCD may follow an acute, episodic or chronic course. In one of the largest follow-up studies, Skoog and Skoog (1999) conducted a 40-year prospective study and reported that approximately 60% of people with OCD displayed signs of general improvement within 10 years of illness, increasing to 80% by the end of the study. However, only 20% achieved full remission even after almost 50 years of illness; 60% continue to experience significant symptoms; 10% displayed no improvement; and 10% had deteriorated. A fifth of those who had displayed an early sustained improvement subsequently relapsed, even after 20 years without symptoms. This suggests that early recovery does not eliminate the possibility of very late relapse. Intermittent, episodic disorder was more common during the early stage of illness and predicted a more favourable outcome, whereas chronic illness predominated in later years. Worse outcome was predicted by early age of onset (particularly in males), experiencing obsessions and compulsions or magical thinking, poor social adjustment and early chronic course.Post-traumatic stress disorderThe onset of symptoms in PTSD is usually in the first month after the traumatic event, but in a minority (less than 15%; McNally, 2003) there may be a delay of months or years before symptoms start to appear. PTSD also shows substantial natural recovery in the initial months and years after a traumatic event. Whereas a high proportion of trauma survivors will initially develop symptoms of PTSD, a substantial proportion of these individuals recover without treatment in the following years, with a steep decline in PTSD rates occurring in the first year (for example, Breslau et al., 1991; Kessler et al., 1995). On the other hand, at least one third of people who initially develop PTSD remain symptomatic for 3 years or longer and are at risk of secondary problems such as substance misuse (for example, Kessler et al., 1995). In the 2007 ONS (McManus et al., 2009) survey, screening positive for current PTSD declined with age, from 4.7% of 16- to 24-year-olds to 0.6% of adults aged 75 years or over.2.2.5. Impairment, disability, secondary problemsDepressionApart from the subjective suffering experienced by people who are depressed, the impact on social and occupational functioning, physical health and mortality is substantial. In fact, depressive illness causes a greater decrement in health state than major chronic physical illnesses such as angina, arthritis, asthma and diabetes (Moussavi et al., 2007).Depression is a major cause of disability across the world. In 1990 it was the fourth most common cause of loss of disability-adjusted life years (DALYs) in the world and by 2020 it is projected to become the second most common cause (World Bank, 1993). In 1994 it was estimated that about 1.5 million DALYs were lost each year in the West as a result of depression (Murray et al., 1994). Depressive disorders account for 4.4% of the global disease burden or the equivalent of 65 million DALYs (Murray & Lopez, 1997; WHO, 2002).Emotional, motivational and cognitive effects substantially reduce a person's ability to work effectively, with losses in personal and family income as well as lost contribution to society in tax revenues and employment skills. Wider social effects include: greater dependence upon welfare and benefits with loss of self-esteem and self-confidence; social impairments, including reduced ability to communicate and sustain relationships during the illness with knock-on effects after an episode; and longer-term impairment in social functioning, especially for those who have chronic or recurrent disorders. Some of the features of depression (such as lethargy) may impede access to appropriate healthcare.Depression can also exacerbate the pain, distress and disability associated with physical health problems, and can adversely affect outcomes. Depression combined with chronic physical health problems incrementally worsens health compared with a physical health problem alone or even combinations of physical health problems (Moussavi et al., 2007). In addition, for a range of physical health problems findings suggest an increased risk of death when comorbid depression is present (Cassano & Fava, 2002). In coronary heart disease, for example, depressive disorders are associated with an 80% increased risk both for its development and of subsequent mortality in people with established disease, at least partly because of common contributory factors (Nicholson et al., 2006).Suicide accounts for nearly 1% of all deaths and nearly two thirds are people with depression (Sartorius, 2001); putting it in another way, having depression leads to over a four-times higher risk of suicide compared with the general population, which rises to nearly 20 times in the most severely ill (Bostwick & Pankratz, 2000). Sometimes depression may also lead to acts of violence against others, and may even include homicide. Marital and family relationships are frequently negatively affected, and parental depression may lead to neglect of children and significant disturbances in children (Ramachandani & Stein, 2003).Generalised anxiety disorderLike major depression GAD is associated with a substantial burden of disability, equivalent to that of other chronic physical health problems such as arthritis and diabetes (Wittchen et al., 2002). There is evidence that comorbid depression and anxiety has a worse prognosis and more persistent symptoms than either depression or anxiety disorders alone (Kroenke et al., 2007). There is also evidence that, in the community, anxiety disorders are independently associated with several physical health problems and that this comorbidity is significantly associated with poor quality of life and disability (Sareen et al., 2006), and high associated health and social costs (Simon et al., 1995).Studies have shown that the presence of GAD is also associated with significant impairments in occupational and social functioning. For example, over 30% of patients with GAD showed an annual reduction of work productivity of 10% or more compared with 8% of people with major depression. The figure for people with comorbid GAD and depression was over 45% (Wittchen et al., 2000). A large part of the economic cost of anxiety disorders is attributable to the costs of non-medical psychiatric treatment. Patients with GAD have increased numbers of visits not only to primary care doctors but also to hospital specialists, particularly gastroenterologists (Kennedy & Schwab, 1997; Wittchen et al., 2002). This may be a consequence of the distressing somatic symptoms that many people with GAD experience.GAD also carries a considerable cost in personal suffering and difficulties. In the Harvard-Brown Program, one third of patients had never married and unemployment was higher than average (Yonkers et al., 1996). Suicidal ideation and suicide attempts are significantly increased in GAD, particularly in women, and this increase is still greater in the presence of comorbid major depression (Cougle et al., 2009).Panic disorderPanic disorder has considerable impact on the NHS, such as general practitioners (GPs), society as a whole (in terms of sickness and absence from work, labour turnover and reduced productivity), and individuals and families (Sherbourne et al., 1996). The impact in any of these spheres is difficult to measure accurately and there may be an underestimation of the impact, but it is still substantial. A person with panic disorder may experience severe and enduring physical sensations, which may lead them to think that they have a physical illness; it can be difficult for healthcare professionals to provide adequate reassurance that this is not the case, which may lead to multiple consultations. Their economic wellbeing may also be affected (Edlund & Swann, 1987).Obsessive-compulsive disorderOCD is ranked by the WHO in the top ten of the most disabling illnesses by lost income and decreased quality of life (Bobes et al., 2001). The severity of OCD differs markedly from one person to another. While some people may be able to hide their OCD from their own family, the disorder may have a major negative impact on social relationships leading to frequent family and marital discord or dissatisfaction, separation or divorce (Koran, 2000). It also interferes with leisure activities (Antony et al., 1998) and with a person's ability to study or work, leading to diminished educational and/or occupational attainment and unemployment (Koran, 2000; Leon et al., 1995). The social cost (that is the person's inability to fully function in society) has been estimated as US$5.9 billion in 1990, or 70.4% of the total economic cost of OCD (DuPont et al., 1995).Post-traumatic stress disorderSymptoms of PTSD cause considerable distress and can significantly interfere with social, educational and occupational functioning. It is not uncommon for people with PTSD to lose their jobs either because re-experiencing symptoms, as well as sleep and concentration problems, make regular work difficult or because they are unable to cope with reminders of the traumatic event they encounter while at work (Zatzick et al., 1997). The resulting financial problems are a common source of additional stress and may be a contributory factor leading to extreme hardship, such as home-lessness. The disorder has adverse effects on the person's social relationships, leading to social withdrawal. Problems in the family and break-up of significant relationships are not uncommon.People with PTSD may also develop further, secondary psychological disorders as complications of the disorder. The most common complications are:the use of alcohol, drugs, caffeine or nicotine to cope with their symptoms, which may eventually lead to dependencedepression, including the risk of suicideother anxiety disorders, such as panic disorder, which may lead to additional restrictions in their life (for example, inability to use public transport).Other possible complications of PTSD include somatisation, chronic pain and poor health (Schnurr & Green, 2003). People with PTSD are at greater risk of physical health problems, including circulatory and musculoskeletal disorders, and have a greater number of medical conditions than those without PTSD (Ouimette et al., 2004).The course and prognosis of all common mental disorders are affected by a range of social factors, a number of which have been already discussed above. However, a range of factors related to social exclusion have a specific effect on access to services. This means that a number of groups may have particular problems accessing services including: those involved with the criminal justice system; homeless or precariously housed people; travelling communities; some groups of younger people (including those who have been in care as children and adolescence); people who misuse drugs and alcohol; and those of uncertain immigration status.2.2.6. Economic costsThe ONS report (McManus et al., 2009) makes the point that although common mental health disorders are usually less disabling than major psychiatric disorders such as psychosis, their greater prevalence means that the cumulative cost to society is vast. Mixed anxiety and depression has been estimated to cause one fifth of days lost from work in Britain (Das-Munshi et al., 2008). Even before the recent expansion of the European Union, it was estimated that work-related stress affected at least 40 million workers in its then 15 member states and that it cost at least €20 billion annually. In the UK, it has been suggested that over 40 million working days are lost each year due to stress-related disorders (European Agency for Safety and Health at Work, 2000).Costs of depressionDepression is associated with high prevalence and treatment costs, and as stated above is considered one of the most important risk factors for suicide (Knapp & Illson, 2002). Furthermore, depression has a large impact on workplace productivity. As a result, depression places an enormous burden on both the healthcare system and the broader society.Depression has a major financial impact on health and social services and the wider economy. A review was conducted by the King's Fund in 2006 to estimate mental health expenditure including depression in England for the next 20 years, to 2026 (McCrone et al., 2008). The study estimated the total cost of services for depression in England in 2007 to be £1.7 billion, while lost employment increased this total to £7.5 billion. Based on the estimate that 1.45 million people would have depression in 2026, the authors estimated that the total service cost would be £12.2 billion when accounting for prescribed drugs, inpatient care, other NHS services, supported accommodation, social services and lost employment in terms of workplace absenteeism.One of the key findings from the cost-of-illness literature is that the indirect costs of depression far outweigh the health service costs. A study by Thomas and Morris (2003) suggested that the effect on lost employment and productivity was 23 times larger than the costs falling to the health service. Other studies have also supported these findings. Based on UK labour-market survey data, Almond and Healey (2003)estimated that respondents with self-reported depression/anxiety were three times more likely to be absent from work (equivalent to 15 days per year) than workers without depression/anxiety. Furthermore, a US-based study suggests that depression is a major cause of reduced productivity at work, in terms of ‘work cut-back days’ (Kessler et al., 2001). This reduced workplace productivity is unlikely to be adequately measured by absenteeism rates and further emphasises the ‘hidden costs’ of depression (Knapp, 2003). A recent study conducted by the the Centre for Economic Performance's Mental Health Policy Group estimated that the total loss of output (in terms of lost productivity, absenteeism from work or benefits received) due to depression and chronic anxiety is some £12 billion per year (Layard, 2006).Other intangible costs of illness include the impact on the quality of life of people with depression and their families and carers. Certainly, the cost-of-illness calculations presented here and in Table 2 show that depression imposes a significant burden on individuals and their families and carers, the healthcare system and the broader economy through lost productivity and workplace absenteeism. Furthermore, it is anticipated that these costs will continue to rise significantly in future years. Therefore, it is important that the efficient use of available healthcare resources is used to maximise health benefits for people with depression.Table 2Summary of cost of illness data for depression and anxiety.Costs of anxiety disordersAnxiety disorders place a significant burden on individuals as well as on the healthcare system. Although direct comparisons between studies are difficult to make due to variations in country, health services and year of interest, economic cost has been estimated at over US$40 billion (Andlin-Sobocki et al., 2005; see Table 2 for further information). Estimated costs are incurred by healthcare resource utilisation such as mental health services, medication, hospitalisation, nursing homes and outpatient visits, productivity losses and, to a lesser extent, by provision of other services such as criminal justice services, social welfare administration and incarceration, as well as family care-giving (0.8%) (Andlin-Sobocki et al., 2005).Total healthcare cost is not the only important outcome to consider when investigating cost. Marciniak and colleagues (2005) found that the total medical cost per person with any anxiety disorder was estimated at US$6,475 in 1999. More specifically, when looking at GAD alone, the figure increased to US$2,138 when controlling for demographics and other disease states. This increased cost may be due to factors such as increased outpatient mental health service use or medical specialist service use. Furthermore, people with anxiety tend to miss more days of work or have a short-term disability than controls (Marciniak et al., 2004).Anxiety disorders are associated with a wide range of comorbidities, which result in a substantial increase in the total healthcare costs. Souêtre and colleagues (1994) estimated the total direct and indirect costs incurred by people with GAD with and without comorbidities using data on 999 people participating in a French cross-sectional study. Controlling for confounding variables, the prevalence of healthcare utilisation in terms of hospitalisation, laboratory tests and medications, and the respective medical costs were found to be significantly higher in people with GAD and other comorbidities than those without comorbidities. Moreover, comorbidities were associated with increased absenteeism from work. In particular, comorbid depression (Marciniak et al., 2005; Wetherell et al., 2007; Zhu et al., 2009) and physical pain (Olfson & Gameroff, 2007; Zhu et al., 2009) have been found to have a significant impact on treatment costs incurred by people with GAD.Costs of post-traumatic stress disorderIn 2003 to 2004, social and welfare costs of claims for incapacitation and severe disablement from severe stress and PTSD amounted to £103 million, which is £55 million more than was claimed 5 years previously (Hansard, 2004). Therefore, PTSD presents an enormous economic burden on families, the national health services and society as a whole.Go to:2.3. TREATMENTA number of treatments exist for common mental health disorders. However, because this guideline is predominantly interested in the identification and assessment of these conditions, the treatments will only be discussed briefly. For more information, please see the relevant guideline (see Section 2.1).2.3.1. Pharmacological treatmentsDepressionThere is a wide range of antidepressant drugs available for people with depression. These can be grouped into tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors and a range of other chemically unrelated antidepressants (British National Formulary [BNF] 59; British Medical Association & the Royal Pharmaceutical Society of Great Britain, 2010).Generalised anxiety disorderPlacebo-controlled trials indicate that a wide range of drugs with differing pharmacological properties can be effective in the treatment of GAD (Baldwin et al., 2005). In recent years, antidepressant medications such as SSRIs have been increasingly used to treat GAD (Baldwin et al., 2005).Conventional antipsychotic drugs and the newer ‘atypical’ antipsychotic agents have also been used in the treatment in GAD, both as a sole therapy and as an ‘addon’ to SSRI therapy when the latter has proved ineffective (Pies, 2009). However, the greater side-effect burden of antipsychotic drugs means that presently their use is restricted to people with refractory conditions, with prescribing being guided by secondary care physicians.Panic disorderThere is evidence to support the use of pharmacological intervention in the treatment of panic disorder, in particular with SSRIs. When a person has not responded to an SSRI, other related antidepressants may be of benefit. There is little good evidence to support the use of benzodiazepines. In contrast to a number of other depressive and anxiety disorders, there is little evidence to support the use of pharmacological and psychological interventions in combination.Obsessive-compulsive disorderPharmacological investigations have demonstrated effectiveness in OCD, in particular with SSRIs and related antidepressants (Montgomery et al., 2001; Zohar & Judge, 1996) for moderate to severe presentations, especially if the problem has a chronic course; this may be in combination with psychological interventions.Post-traumatic stress disorderAt present there is no conclusive evidence that any drug treatment helps as an early intervention for the treatment of PTSD-specific symptoms (NCCMH, 2005). However, for people who are acutely distressed and may be experiencing severe sleep problems, consideration may be given to the use of medication. Drug treatments for PTSD should not be used as a routine first-line treatment for adults (in general use or by specialist mental health professionals) in preference to a trauma-focused psychological therapy. Drug treatments should be considered for the treatment of PTSD in adults when a person with the disorder expresses a preference not to engage in a trauma-focused psychological treatment. The SSRI paroxetine is the only drug with a current UK product licence for PTSD.2.3.2. Psychological treatmentsDepressionEffective psychological treatments for depression identified in the NICE Depression guideline (NICE, 2009a) include: cognitive behavioural therapy (CBT), behavioural activation, interpersonal therapy (IPT),behavioural couples therapy and mindfulness-based cognitive therapy. For moderate to severe disorders these are often provided in conjunction with antidepressants. For subthreshold and milder disorders, structured group physical activity programmes, facilitated self-help and CCBT are effective interventions.Generalised anxiety disorderCognitive and behavioural approaches are the treatments of choice for GAD. People who have moderate to severe disorder, particularly if the problem is long-standing, should be offered CBT or applied relaxation. For those with milder and more recent onset disorders, two options are available: facilitated ornon-facilitated self-help based on CBT principles and psychoeducational groups also based on CBT principles.Panic disorderCognitive and behavioural approaches are again the treatments of choice for panic disorder. People who have a moderate to severe GAD, particularly if it is longstanding, should receive between 7 and 14 hours of therapist-provided treatment over a 4-month period. For those with milder and more recent onset GAD, facilitated or non-facilitated self-help based on CBT principle are efficacious treatments.Obsessive-compulsive disorderCBT is the most widely used psychological treatment for OCD in adults (Roth & Fonagy, 2004). The main CBT interventions that have been used in the treatment of OCD are exposure and response prevention (ERP) (for example, Foa & Kozak, 1996; Marks, 1997), different variants of cognitive therapy (Clark, 2004; Freeston et al., 1996; Frost & Steketee, 1999; Krochmalik et al., 2001;Rachman, 1998, 2002 and 2004; Salkovskis et al., 1999; van Oppen & Arntz, 1994; Wells, 2000), and a combination of ERP and cognitive therapy (see Kobak et al., 1998; Roth & Fonagy, 2004). ERP and cognitive therapy have different theoretical underpinnings, but may be used together in a coherent package.Post-traumatic stress disorderGeneral practical and social support and guidance about the immediate distress and likely course of symptoms should be given to anyone following a traumatic incident. Trauma-focused psychological treatments are effective for the treatment of PTSD, either trauma-focused CBT or eye movement desensitisation and reprocessing (EMDR). These treatments are normally provided on an individual outpatient basis and are effective even when considerable time has elapsed since the traumatic event(s).2.3.3. Current levels of treatment of common mental health disordersIt is concerning that, according to the 2007 ONS survey (McManus et al., 2009), only one quarter (24%) of people with a disorder were receiving any treatment for it in the week prior to interview. Treatment received by that 24% was mostly in the form of medication: 14% were taking psychoactive medication only, 5% were in receipt of counselling or therapy and 5% were receiving both medication and counselling/therapy.Use of healthcare servicesOf the people reporting a common mental health disorder in the ONS survey (McManus et al., 2009), 39% had used some type of healthcare service for a mental or emotional problem within the last year, compared with 6% of men and women without a disorder.Primary care servicesGeneral practice services were the most common healthcare service used in the ONS survey. A total of 38% of people with a common mental health disorder contacted their GP for help. Depression and phobias were associated with the highest use of healthcare services for a mental or emotional problem (both 67%), and mixed anxiety and depression was associated with the lowest use (30%) (McManus et al., 2009).Community care servicesAll respondents in the ONS survey (McManus et al., 2009), were asked about community and day care services used in the past year. Community and day care services were used less than healthcare services. Those with phobias made most use of community or day care services (49%), while mixed anxiety and depressive disorder was associated with the lowest rate of community or day care service use (12%).SummaryIn summary, common mental health disorders are associated with a range of symptoms that can lead to significant impairment and disability, and high costs both for the individual with the disorder and for society as a whole.Effective treatments are available that differ depending on the disorder. As a result, early detection, assessment and intervention are key priorities for any healthcare system. This guideline, which is focused on primary care, will provide recommendations on how to best identify and assess common mental health disorders and the key indicators for treatment in order to help improve and facilitate access to care, and the route through care.Go to:2.4. IDENTIFICATION, ASSESSMENT AND PATHWAYS TO CAREGoldberg and Huxley (1992) described a useful model within which to consider issues relating to the identification, assessment and pathway to psychiatric care for people with a common mental health disorder (see Figure 1). They identified five levels of care, with ‘filters’ between them relating to the behaviour of those with the disorders and the behaviours of the healthcare practitioners with whom they came into contact, emphasising that only a small proportion of people with a mental disorder receive specialist psychiatric care.Figure 1Levels and filters model of the pathway to psychiatric care (adapted from Goldberg & Huxley, 1992).The prevalence rates given above are taken from the original model and relate to proportions found in epidemiological surveys conducted before 1980. The Level 1 figures refer to all psychiatric disorders in the population, including psychotic and organic disorders, so the prevalence rates are somewhat higher than those given for the common mental health disorders in Section 2.2.2 above.For Filter 1 (the decision to consult a primary care physician), the key individual is the patient themselves. Level 2 refers to all psychiatric disorders in general practice, even if the GP has not diagnosed the disorder. Filter 2 refers to the detection and diagnosis of psychiatric disorder; Level 3 is ‘conspicuous’ or diagnosed psychiatric disorder within primary care. The third filter is the process of referral to secondary care, and Level 4 and Level 5 refer to the small proportion of patients with illnesses severe enough to need specialist secondary care.2.4.1. Increasing access to careThere are significant concerns about a number of barriers to access to care. These may include stigma (both cultural and self, and stigmatisation), misinformation or cultural beliefs about the nature of mental disorder, social policy or other approaches that limit access to services.Presentation of people with a common mental health disorder to primary careOf the 130 cases of depression (including mild cases) per 1000 population, only 80 will consult their GP. The stigma associated with mental health problems generally (Sartorius, 2002), and the public view that others might view a person with depression as unbalanced, neurotic and irritating (Priest et al., 1996), may partly account for the reluctance of depressed people to seek help (Bridges & Goldberg, 1987). The most common reasons given for reluctance to contact the family doctor include: did not think anyone could help (28%); a problem one should be able to cope with (28%); did not think it was necessary to contact a doctor (17%); thought problem would get better by itself (15%); too embarrassed to discuss it with anyone (13%); and afraid of the consequences (for example treatment, tests, hospitalisation or being sectioned under the Mental Health Act; 10%) (Meltzer et al., 2000).Most anxiety disorders are found more frequently in primary care than in the community except for social anxiety disorder and agoraphobia, both of which involve avoidance of public places such as doctors' surgeries (Bushnell et al., 2005; Oakley Browne et al., 2006; see Table 3). However, even when people with anxiety and depression do consult their GP, their disorder often goes unrecognised, partly because many do not present their psychological symptoms overtly.Table 3Twelve-month prevalence of anxiety disorders in New Zealand (Oakley Browne et al., 2006).Dowrick and colleagues (2010) carried out systematic reviews to identify groups for whom there are particular problems accessing mental health services, and to identify systems for promoting access. Poorer access to care has been found to be associated with lower social class, geographical location, ethnic minority groups, the presence of sensory or other impairments, the presence of learning difficulties, and particular demographic factors including age and gender (for example, older people or younger men).This guideline seeks to identify service developments or changes that may be specifically designed to promote access, both for the general population and for specific outreach groups (see Chapter 4). Particular areas include: community outreach; providing education and information concerning the nature of mental disorder; and new and adapted models of service delivery, which focus on the needs of black and minority ethnic (BME) groups and older people.2.4.2. IdentificationRecognition of depressionOf the 80 people with depression per 1000 population who do consult their GP, 49 are not recognised as depressed, mainly because most such patients are consulting for a somatic symptom and do not consider themselves mentally unwell despite the presence of symptoms of depression (Kisely et al., 1995). People who present with somatic symptoms are especially unlikely to be recognised (Kisely et al., 1995). GPs tend to be better at recognising more severe forms of the disorder (Goldberg et al., 1998; Thompson et al., 2001). With 50% of people with depression never consulting a doctor, 95% never entering secondary mental health services, and many more having their depression going unrecognised and untreated, this is clearly a problem for primary care.Recognition of anxiety disordersAnxiety symptoms are also often not recognised by primary healthcare professionals because, once again, patients may not complain of them overtly (Tylee & Walters, 2007). Cases of anxiety are especially likely to be missed when people frequently attend with multiple symptoms, despite reassurance. Instead, these symptoms are often characterised as possible symptoms of cardiovascular, respiratory, gastrointestinal, neurological or musculoskeletal disease (Blashki et al., 2007).For many people with a common mental health disorder, stigma and avoidance may contribute to under-recognition of their condition. Pessimism about possible treatment outcomes may further contribute to this. However, GPs themselves can contribute to the under-recognition of these conditions.Consultation skillsGPs are immensely variable in their ability to recognise depressive illnesses, with some recognising virtually all of the patients found to be depressed at independent research interview, and others recognising very few (Goldberg & Huxley, 1992; Üstün & Sartorius, 1995).The communication skills of the GP make a vital contribution to determining their ability to detect emotional distress, and those with superior skills allow their patients to show more evidence of distress during their interviews thus facilitating detection (Goldberg & Bridges, 1988; Goldberg et al., 1993).According to Goldberg and colleagues (1980a and 1980b), ten behaviours are associated with greater detection. These include factors such as making eye contact, having good interview skills, asking well-formulated questions and focusing on more than just a symptom count. Attempts to improve GP behaviour have been successful (Ostler et al., 2001; Tiemens et al., 1999), although results are mixed (Kendrick et al., 2001; Thompson et al., 2000) and interventions sometimes fail to impact on patient outcomes despite changes in clinician behaviour (Gask et al., 2004).Case identificationThe fact that common mental health disorders often go undiagnosed among primary care attenders has led to suggestions that clinicians should systematically screen for hidden disorders. However, general screening is not without its problems and is currently not recommended in most countries, including the UK. Instead, targeted case identification, which involves screening a smaller group of people known to be at higher risk based on the presence of particular risk factors, may be a more useful method of improving recognition of psychological disorders in primary care.Whooley and colleagues (1997) found that two questions were particularly sensitive in identifying depression:During the last month, have you often been bothered by feeling down, depressed or hopeless?During the last month, have you often been bothered by having little interest or pleasure in doing things?The current NICE Depression guideline (NICE, 2009a) recommends that GPs be alert to possible depression in at-risk patients and consider asking the above Whooley questions when depression is suspected. If the person screens positive, further follow-up assessments should then be considered. Currently, no equivalent Whooley questions have been recommended for anxiety.The view of the GDG for this guideline was that the development of separate case identification questions for each type of anxiety disorder would very likely be impractical and have no utility for routine use in primary care. The preference was to explore the possibility of a small number of case identification questions with general applicability for a range of anxiety disorders. A potentially positive response would then prompt a further assessment. This is dealt with in Chapter 5.2.4.3. AssessmentSince April 2006, the UK general practice contract Quality and Outcomes Framework Guidance for GMS Contract (QOF) has incentivised GPs for measuring the severity of depression at the outset of treatment in all diagnosed cases, using validated questionnaires (British Medical Association & NHS Employers, 2008). The aim is to improve the targeting of treatment of diagnosed cases, particularly antidepressant prescribing, to those with moderate to severe depression, in line with the NICE guidelines.A number of assessment tools have been identified as potentially useful for the assessment. The NICEDepression guideline (NICE, 2009a), for example, recommends the use of the nine-item Patient Health Questionnaire (PHQ-9) (Spitzer et al., 1999), the depression scale of the Hospital Anxiety and Depression Scale (HADS) (Zigmond & Snaith, 1983) and the Beck Depression Inventory, 2nd edition (BDI-II) (Beck, 1996; Arnau et al., 2001). The rationale for using such instruments is that doctors' global assessments of severity do not agree well with valid and reliable self-report measures of severity in terms of cut-off levels for case identification (Dowrick, 1995; Kendrick et al., 2005; Lowe et al., 2004;Williams et al., 2002), which can result in over-treatment of mild cases and under-treatment of moderate to severe cases (Kendrick et al., 2001 and 2005).However, the QOF guidance, again in line with NICE guidance, also recommends that clinicians consider the degree of associated disability, previous history and patient preference when assessing the need for treatment rather than relying completely on the questionnaire score (British Medical Association & NHS Employers, 2006). This is especially important given that people with mental illness vary in the pattern of symptoms they experience, their family history, personalities, pre-morbid difficulties (for example, sexual abuse), physical illness, psychological mindedness, current relational and social problems and comorbidities – all of which may affect the outcomes of any intervention (for example, Cassano & Fava, 2002; Ramachandani & Stein, 2003).Currently, evidence exists that points practitioners in the direction of well-validated tools. As a result, this guideline will not attempt to recommend specific tools because preferences vary between practices. Instead, this guideline will focus on ways to improve the assessment process, specifically, how to assess the nature and severity of a common mental health disorder, factors that may influence referral for treatment, routine outcome monitoring (ROM) and risk assessment.2.4.4. Pathways to careGiven the complexity of healthcare organisations and the variation in the way care is delivered (inpatient, outpatient, day hospital, community teams and so on), choosing the right service configuration for the delivery of care to specific groups of people has gained increasing interest with regard to both policy (for example, see Department of Health, 1999) and research (for example, evaluating day hospital treatment [Marshall et al., 2001]). Research using randomised controlled trial (RCT) designs has a number of difficulties; for example, using comparators such as ‘standard care’ in the US makes the results difficult to generalise or apply to countries with very different types of ‘standard care’.Stepped careCurrently, much of the UK mental health system is organised around the principles of stepped care. Stepped care (Scogin et al., 2003) is a framework that is increasingly being used in the UK to provide a structure for best-practice clinical pathways to care. It is designed to increase the efficiency of service provision with an overall benefit to patient populations. The basic principle is that patients presenting with a common mental health disorder will ‘step through’ progressive levels of treatment as necessary, with the expectation that many of these patients will recover during the less intensive phases. High-intensity treatments are reserved for patients who do not benefit from low-intensity treatments, or for those who can be accurately predicted not to benefit from such treatments. Thus, stepped care has the potential for deriving the greatest benefit from available therapeutic resources (Bower & Gilbody, 2005) and has been recommended in a number of NICE guidelines including Depression (NICE, 2009a) and Generalised Anxiety Disorder and Panic Disorder (With or Without Agoraphobia) in Adults (NICE, 2011a).A potential disadvantage of a stepped-care approach is that patients who do not benefit from low-intensity treatments may still have to undergo such treatments before a successful outcome is achieved. To maximise the efficiency of care delivery, patients who can be predicted as unlikely to respond to less intensive treatments ideally should be referred straight to higher levels; that is, care should be ‘stratified’ to an extent (Bower et al., 2006). However, prognostic evidence to support such decisions is currently lacking.Improving Access to Psychological Therapies programmeIn 2004 the economist Richard Layard made the case for a major expansion in the availability of psychological treatments, which he suggested could bring a significant reduction in the welfare benefits bill and increased tax contributions of those helped back to work. In 2006 the government established the Improving Access to Psychological Therapies (IAPT) programme, based heavily on the stepped-care approach. Clark and colleagues (2009) reported on the initial success of two demonstration sites in Newham and Doncaster, and the IAPT programme proposes a phased national roll-out by 2013 (to date, over 50% of Primary Care Trusts have an IAPT service). Self-referral to IAPT services is also actively encouraged, with emerging evidence to suggest that it increases access for vulnerable groups, such as BME groups to psychological interventions (Clark et al., 2009). In addition, an analysis of the first full year of operation of the first wave of roll-out sites (October 2008 to September 2009) has recently been published (Glover et al., 2010). Anonymous patient-level data were collected from 32 sites with the aim of evaluating whether the ‘commitments relating to accessibility, the provision of NICE-approved therapies and detailed outcome monitoring were progressing appropriately’. The authors concluded that the large amount of outcome data collected is a remarkable achievement, although there are some limitations and shortcomings that need to be addressed. For example, the analysis suggests that the diagnostic coding frame needs to be extended to include panic disorder and more research needs to be conducted to establish how reliable diagnoses can be obtained. Furthermore, in terms of equality of access, the authors state that ‘older people and men appeared under-represented in relation to expectation based on the patterns of morbidity shown by the psychiatric morbidity survey. The position for people with disabilities is not recorded at all in most sites, making it difficult to see how commissioners and providers can discharge their responsibilities to promote access to services for disabled people under disability discrimination legislation.’ Also, ‘after allowing for all other relevant factors for which data were available, Black people were significantly less likely to receive any treatment or to recover on either the two-scale or the three-scale makers, Asians were less likely to receive high intensity treatment (CBT or counselling), and both were significantly less likely to receive CBT’. More generally, with regard to treatment received, there was evidence to suggest that more needs to be done to ensure that the treatment given for specific diagnoses is aligned to that recommended in NICE guidelines.