Association between alcohol flushing syndrome and cancer: A systematic review and meta-analysis.

Introduction: Alcohol flushing syndrome (AFS) is experienced by up to 46% of East Asians. This study aimed to review the risk of cancers in AFS patients, elucidate an exposure-response relationship, and understand risk associated with alcohol intake and cancer. Method: An electronic database search of PubMed, Embase, Scopus and Cochrane Library was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Observational studies on AFS' effects and all cancers risk were included. Studies including patients with existing malignancy were excluded. Dichotomous variables were pooled using the Mantel-Haenszel method with a random effects model. Sensitivity and subgroup analyses were performed. PROSPERO (CRD42023392916) protocol was followed. Results: A total of 18 articles were included in the final analysis with a total of 387,521 participants. AFS was associated with an increased risk of all cancers (odds ratio [OR] 1.19, 95% confidence interval [CI] 1.06-1.34), esophageal squamous cell carcinoma (OR 1.47, 95% CI 1.05-2.05) and gastric adenocarci-noma (OR 1.40, 95% CI 1.14-1.72). Men with AFS exhibited an increased risk of all cancers (OR 1.34, 95% CI 1.13-1.59). However, this was not observed in women. All cancers risk was associated with AFS in those who consumed drink (i.e. consumed alcohol) more than 200 g of pure ethanol/week (OR 1.68, 95% CI 1.20-2.37) but not those who consumed less than 200 g of pure ethanol/week (OR 1.27, 95% CI 0.90-1.79) or non-drinkers (OR 0.99, 95% CI 0.67-1.47). Conclusion: AFS is associated with an increased risk of all cancers, particularly esophageal squamous cell carcinoma and gastric adenocarcinoma.

Epidemiologic relationship between alcohol flushing and smoking in the Korean population: the Korea National Health and Nutrition Examination Survey.

Although facial flushing after drinking alcohol (alcohol flushing response) is common in Asian populations, the epidemiological features in a large sample have been investigated in only a few studies. This study assessed the epidemiologic characteristics and associated factors for alcohol flushing in a Korean population. This study was based on data collected during the 2019 Korea National Health and Nutrition Examination Survey (KNHANES). A total of 5572 Korean adults was included in the general population group, and the alcohol flushing group consisted of 2257 participants. Smoking and physical activity were evaluated as possible associated factors for alcohol flushing. The overall prevalence of alcohol flushing was estimated at 40.56% of the general population (43.74% in males and 37.4% in females), and the prevalence was highest at 60-69 years of age and lowest in individuals older than 80 years. Occasional, frequent, and persistent alcohol flushing was reported by 11.9%, 3.7% and 15.0% of current flushers, among whom persistent flushers consumed the least amount of alcohol. Subjects who currently smoke had a higher propensity of alcohol flushing (adjusted OR 1.525, 95% CI 1.2-1.938), and subjects with smoking history of 20-29 pack-years (PYs) showed the highest association (adjusted OR 1.725, 95% CI 1.266-2.349) with alcohol flushing after adjustment for confounders. In contrast, significant association was not found between physical activity and alcohol flushing. The results demonstrated that current smoking status is shown to be significantly associated with alcohol flushing, and that current smokers with a history of smoking ≥ 20 PYs had a higher likelihood of alcohol flushing than non-smokers or ex-smokers.

Impact of Alcohol-Induced Facial Flushing Phenotype on Alcohol Consumption Among Korean Adults: 2-Year Cross-Sectional Study.

BACKGROUND: The alcohol-induced facial flushing phenotype (flushing) is common among East Asians. Despite a small intake of alcohol, they experience heightened levels of acetaldehyde, a group-1 carcinogen, which, in turn, causes unpleasant symptoms such as redness, acting as a robust protective mechanism against consuming alcohol. However, some individuals with this genetic trait exhibit weakened alcohol restraint, which increases the risk of developing alcohol-related cancers, such as esophageal and head or neck cancer, by several times. Although this flushing phenomenon is crucial for public health, there is a paucity of studies that have comprehensively investigated the effect of flushing or its genotype on alcohol consumption in a large group of East Asians while controlling for various sociodemographic and health-related variables at a country level. OBJECTIVE: This 2-year cross-sectional study aims to explore the effect of flushing on drinking behavior in Koreans and to examine whether the effect varies across sociodemographic and health-related factors. METHODS: We used data from the Korea National Health and Nutrition Examination Survey (KNHANES) for 2019 and 2020 conducted by the Korea Disease Control and Prevention Agency. Our sample comprised 10,660 Korean adults. The study investigated the association of 26 variables, including flushing, with drinking frequency and amount. The effect of flushing was examined with and without adjusting for the other 25 variables using multinomial logistic regression analysis. In addition, we tested the interaction effect with flushing and conducted a simple effect analysis. We used complex sample design elements, including strata, clusters, and weights, to obtain unbiased results for the Rao-Scott χ2 test, 2-tailed t test, and multinomial logistic regression analysis. RESULTS: The suppressive effect of flushing was significant (P<.001) across all pronounced categories of alcohol consumption in 2019. The ranges of standardized regression slopes and odds ratios (ORs) were -6.70≥ß≥-11.25 and 0.78≥OR≥0.50 for frequency and -5.37≥ß≥-17.64 and 0.73≥OR≥0.36 for amount, respectively. The effect became somewhat stronger when adjusted for confounders. The effect also exhibited an overall stronger trend as the severity of alcohol consumption increased. The ß values and ORs were consistently smaller in 2020 compared to the previous year. A simple effect analysis revealed a diminished alcohol-suppressive effect of flushing on alcohol consumption for specific groups (eg, those with low levels of education, limited family support, physical labor, or health-related issues). CONCLUSIONS: Our findings suggest that flushing suppresses drinking in Koreans overall but has little or no effect in certain susceptible populations. Therefore, health authorities should conduct targeted epidemiological studies to assess drinking patterns and disease profiles, particularly regarding alcohol-related cancers, and establish effective preventive measures tailored to this population.

Asian flush is a potential protective factor against COVID-19: a web-based retrospective survey in Japan.

BACKGROUND: Coronavirus disease 2019 (COVID-19), first reported in December 2019, spread worldwide in a short period, resulting in numerous cases and associated deaths; however, the toll was relatively low in East Asia. A genetic polymorphism unique to East Asians, Aldehyde dehydrogenase 2 rs671, has been reported to confer protection against infections. METHOD: We retrospectively investigated the association between the surrogate marker of the rs671 variant, the skin flushing phenomenon after alcohol consumption, and the timing of COVID-19 incidence using a web-based survey tool to test any protective effects of rs671 against COVID-19. RESULTS: A total of 807 valid responses were received from 362 non-flushers and 445 flushers. During the 42 months, from 12/1/2019 to 5/31/2023, 40.6% of non-flushers and 35.7% of flushers experienced COVID-19. Flushers tended to have a later onset (Spearman's partial rank correlation test, p = 0.057, adjusted for sex and age). Similarly, 2.5% of non-flushers and 0.5% of flushers were hospitalized because of COVID-19. Survival analysis estimated lower risks of COVID-19 and associated hospitalization among flushers (p = 0.03 and <0.01, respectively; generalized Wilcoxon test). With the Cox proportional hazards model covering 21 months till 8/31/2021, when approximately half of the Japanese population had received two doses of COVID-19 vaccine, the hazard ratio (95% confidence interval) of COVID-19 incidence was estimated to be 0.21 (0.10-0.46) for flusher versus non-flusher, with adjustment for sex, age, steroid use, and area of residence. CONCLUSIONS: Our study suggests an association between the flushing phenomenon after drinking and a decreased risk of COVID-19 morbidity and hospitalization, suggesting that the rs671 variant is a protective factor. This study provides valuable information for infection control and helps understand the unique constitutional diversity of East Asians.

Association between changes in facial flushing and hypertension across drinking behavior patterns in South Korean adults.

Heavy alcohol drinking has been reported to be associated with hypertension. Moreover, when drinking alcohol, individuals may experience symptoms such as facial flushing. Therefore, this study aimed to examine the association between changes in facial flushing and hypertension across different drinking behavior patterns in South Korean adults. Data from the Korea Community Health Survey conducted in 2019 were used, and 118 129 (51 047 men and 67 082 women) participants were included. The participants were divided into five groups based on the change in facial flushing (non-drinking, non-flushing to non-flushing, flushing to flushing, non-flushing to flushing, flushing to non-flushing). The risk of hypertension in each facial flushing group was analyzed by multiple logistic regression. Men in the non-flushing to flushing group had a significantly higher association with hypertension than other groups (men: odds ratio (OR) 1.42, confidence interval (CI) 1.14-1.76). According to the level of alcohol use disorder, the non-flushing to flushing group showed a significantly increased odds of hypertension compared to all levels of drinking (men: mild drinking: OR 1.95, CI 1.40-2.71; moderate drinking: OR 2.02, CI 1.41-2.90; women: moderate drinking: OR 1.71, CI 1.16-2.52; heavy drinking: OR 1.90, CI 1.19-3.04). This study found a significant association between changes in facial flushing and hypertension among adults in South Korea. In particular, individuals who changed from non-flushing to flushing reactions had an increased association with hypertension than the other groups. Compared to people at the same drinking level, people with non-flushing to flushing reactions were highly associated with hypertension at moderate drinking level.

Alcohol Consumption and Cigarette Smoking among Young Adults: An Instrumental Variable Analysis Using Alcohol Flushing.

Association between drinking and smoking has remained controversial since the association between two studies were influenced by various confounding. Thus, our study aimed to explore the causal effect of alcohol consumption and cigarette smoking using alcohol flushing as an instrument variable, which is free from confounders. We analyzed cross-sectional survey data from 2500 Korean young adults (1600 men and 900 women). Alcohol flushing was strongly associated with log transformed alcohol consumption (F = 272). In men, alcohol non-flushers were 1.41 times (95% CI 1.28-1.55) more likely to smoke 100 cigarettes in their lifetime in logistic regression analysis. Alcohol non-flushers were also 1.3 times (95% CI 1.21-1.40) more likely to become daily smokers and 1.39 times (95% CI 1.27-1.51) more likely to be current smokers than alcohol flushers. However, in an IV analysis, no causal relationships between alcohol consumption and smoking status were found. Alcohol consumption, on the other hand, was causally associated with lowering nicotine dependence and former smoking in men. Alcohol consumption determined by alcohol flushing status does not appear to be causally linked to the smoking behavior of young adults. The relationship between alcohol consumption and nicotine dependence and smoking cessation needs further study.

Broncoespasmo y flushing tras la vacunación con neumococo polisacárida de 23 serotipos en pacientes crónicos / Bronchospasm and flushing after vaccination with 23 serotype pneumococcal polysaccharide in chronic patients

Objetivos: Describir las características clínico-epidemiológicas en una serie de casos de sospecha de reacciones adversas sistémicas registradas tras la administración de la vacuna frente a neumococo polisacárida de 23 serotipos (PNEUMOVAX23(R)). Calcular la incidencia acumulada de dicha reacción y conocer si se han descrito casos similares y/o compatibles en la literatura científica o en Farmacovigilancia. Métodos: Estudio observacional retrospectivo realizado entre 01/12/2015 y 30/09/2017 en la Unidad de Vacunas de un hospital autonómico de referencia. Se calculó la incidencia acumulada de la reacción adversa sistémica para esa vacuna. Se consultó la base de datos del Sistema Español de Farmacovigilancia (FEDRA). Resultados: Se registraron 9 sospechas de reacciones adversas sistémicas inmediatas (flushing + broncoespasmo + SatO2<95%). La incidencia acumulada fue 1,036%. El desenlace fue recuperado/resuelto para todos. No se encontraron casos similares y/o compatibles. Conclusiones: Las reacciones descritas no constan en la ficha técnica de PNEUMOVAX23(R). Epidemiológicamente no se puede establecer ninguna relación causal entre la aparición de los síntomas y las variables estudiadas. Esta información podría ser la base de investigaciones más amplias que supusieran la posible modificación de la ficha técnica

Objectives: To describe the clinical-epidemiological characteristics of a series of suspected systemic adverse reactions registered with the 23 serotype pneumococcal polysaccharide vaccine (PNEUMOVAX23(R)). Calculate the cumulative incidence of the reaction and know if similar and/or compatible cases have been described in the scientific literature or in pharmacovigilance. Methods: Observational and retrospective study realized between 01/12/2015 and 30/09/2017 in the Vaccines Unit of an autonomic reference hospital. We calculated the cumulative incidence of the adverse reaction for that vaccine. The common pharmacovigilance database (FEDRA) was consulted. Results: Nine systemic adverse reactions were recorded (flushing + bronchospasm + SatO2<95%). The cumulative incidence was 1.036%. The outcome was recovered/resolved for everyone. No similar and/or compatible cases were found. Conclusions: The reactions described do not appear in the PNEUMOVAX23(R) data sheet. Epidemiologically, no causal relationship can be established between the symptoms and the variables studied. This study could be the basis for more detailed research that could modify the vaccine data sheet

[Bronchospasm and flushing after vaccination with 23 serotype pneumococcal polysaccharide in chronic patients]. / Broncoespasmo y flushing tras la vacunación con neumococo polisacárida de 23 serotipos en pacientes crónicos.

OBJECTIVE: To describe the clinical-epidemiological characteristics of a series of suspected systemic adverse reactions registered with the 23 serotype pneumococcal polysaccharide vaccine (PNEUMOVAX23®). Calculate the cumulative incidence of the reaction and know if similar and/or compatible cases have been described in the scientific literature or in pharmacovigilance. METHODS: Observational and retrospective study realized between 01/12/2015 and 30/09/2017 in the Vaccines Unit of an autonomic reference hospital. We calculated the cumulative incidence of the adverse reaction for that vaccine. The common pharmacovigilance database (FEDRA) was consulted. RESULTS: Nine systemic adverse reactions were recorded (flushing + bronchospasm + SatO2<95%). The cumulative incidence was 1.036%. The outcome was recovered/resolved for everyone. No similar and/or compatible cases were found. CONCLUSIONS: The reactions described do not appear in the PNEUMOVAX23® data sheet. Epidemiologically, no causal relationship can be established between the symptoms and the variables studied. This study could be the basis for more detailed research that could modify the vaccine data sheet.

Primary Reason for Drinking Among Current, Former, and Never Flushing College Students.

Alcohol consumption among individuals who experience a flushing response (reddening of the face, nausea, dizziness, headache, anxiety, and increased heartbeat) can result in serious health problems. However, studies on reasons for drinking among flushers, especially in the college context, are limited. Thus, this study investigated the association between primary reason for drinking and alcohol use among a nationally representative sample of current, former, and never flushing college students. The aim was to measure whether college students with current or former experience of facial flushing have different primary reasons for drinking compared to students with no experience of facial flushing. We surveyed and analyzed the data of 4590 students in a nationally representative sample of 82 colleges in South Korea. Multiple regression analysis was used to identify the association between primary reason for drinking and alcohol intake. Alcohol intake was measured using the Alcohol Use Disorders Identification Test (AUDIT). Among 1537 current (33.5%), 152 former (3.3%), and 2901 (63.2%) never flushers, mean AUDIT scores were 7.715 ± 5.434, 11.039 ± 6.405, and 10.465 ± 5.779, respectively. Current flushers had significantly higher AUDIT scores when drinking for pleasure (ß = 2.696, p < 0.0001) or stress/depression (ß = 2.578, p < 0.0001). Primary reasons for drinking were not associated with alcohol intake for former flushers. Never flushers had significantly higher AUDIT scores when drinking for pleasure (ß = 2.696, p < 0.0001), stress/depression (ß = 2.578, p < 0.0001), or boredom (ß = 0.740, p = 0.029) than peer pressure. Our results suggest that former and never flushers consume higher amounts of alcohol on average than never flushers. For current flushers, drinking for pleasure or stress/depression may increase alcohol intake, while for never flushers, drinking for pleasure, stress/depression, as well as boredom may have the same effect.

The Jarisch-Herxheimer reaction in syphilis: could molecular typing help to understand it better?

OBJECTIVES: The Jarisch-Herxheimer reaction (JHR) is a febrile inflammatory reaction that may occur in patients after treatment of syphilis. The overall rate is estimated to be 10-25% with broad variations over time. It appears to be related to factors like stage of the disease or reagin titres. In this study, we aimed to describe the incidence of and risk factors including strain typing for JHR among patients with syphilis. METHODS: From January through October 2015, 224 consecutive patients (82 of them with HIV) who were diagnosed with early syphilis were enrolled in this prospective observational study in a referral STI clinic in Barcelona. An appointment was offered to them after 10-14 days of treatment to inquire about the reaction with the use of a standardized form. Treponema pallidum molecular typing was made to detect a possible strain related to reaction. RESULTS: Overall, 28% of patients developed JHR. This varied from 56% in secondary, 37% in primary to 7% in early latent syphilis. The most frequent types of reaction were fever (57.5%) and worsening of the lesions (31%). The median time to development of JHR was 6 h [IQR 4-10 h] and lasted a median of 9 h [IQR 4-24 h]. The JHR was less probable in early latent compared to primary/secondary syphilis (P = 0.04) and in patients treated with doxycycline compared to those treated with penicillin (P = 0.01). No differences were seen regarding reagin titres or HIV status, and no association with a specific strain was found. CONCLUSIONS: In this study, JHR occurred in a similar frequency as in other contemporary studies. Symptomatic syphilis and treatment with penicillin were associated with an increased risk of JHR, whereas the previous episode of syphilis was associated with a low risk of it. We could not find associations with specific strains of T. pallidum.

Cigarette smoking, alcohol drinking, and oral cavity and pharyngeal cancer in the Japanese: a population-based cohort study in Japan.

The effects of cigarette smoking and alcohol drinking on the incidence of oral cavity and pharyngeal cancer (OCPC) in the Asian population have been poorly understood. To assess the effects of cigarette smoking, alcohol drinking, and facial flushing response on incidence of OCPC, a total of 95 525 middle-aged and older eligible individuals were followed in a large-scale population-based cohort study in Japan from 1990 to 2010. In this study, the person-years of observation were 698 006 in men and 846 813 in women, and a total of 222 cases (men=160, women=62) of OCPC were newly diagnosed during the study period. A multivariate Cox proportional-hazards model was used to assess the incidence risk of OCPC and subsites by cigarette smoking and alcohol drinking. The result showed that cigarette smoking and regular alcohol drinking were associated significantly with the incidence of OCPC in men. Compared with nonsmokers and nondrinkers, current male smokers showed a hazard ratio (HR) of 2.37 [95% confidence interval (CI)=1.51-3.70] and regular male drinkers showed an HR of 1.82 (95% CI=1.20-2.76). Cigarette smoking also increased the risk of OCPC among male heavy alcohol drinkers (HR=4.05, 95% CI=2.31-7.11). However, there was no significant association between facial flushing response and OCPC. In conclusion, cigarette smoking and alcohol drinking are independent risk factors for OCPC and its subsites in the male Japanese population.

Validation of Alcohol Flushing Questionnaires in Determining Inactive Aldehyde Dehydrogenase-2 and Its Clinical Implication in Alcohol-Related Diseases.

BACKGROUND: Our aim was to validate alcohol flushing questionnaires in detecting inactive ALDH2 (ALDH2*1/*2 or ALDH2*2/*2). METHODS: Two study sets were established; in study set 1, 210 healthy male subjects (age 22 to 59 years) were enrolled; in study set 2, 756 subjects were enrolled who received esophagogastroduodenoscopy to evaluate their dyspeptic symptoms or as part of a gastric cancer screening program. Subjects in study sets 1 and 2 completed the modified alcohol flushing questionnaires of Yokoyama and colleagues (, ). Polymerase chain reaction-restriction fragment length polymorphism method was used to determine ALDH2 genotype. RESULTS: In study set 1, 29.0% (61 of 210) had inactive ALDH2. The sensitivity and specificity of the modified alcohol flushing questionnaire for detecting inactive ALDH2 were 95.1 and 76.5%, respectively. Drinking problems negatively correlated with positive alcohol flushing response and inactive ALDH2 (all p-values < 0.05). In study set 2, the sensitivity and specificity of the alcohol flushing questionnaire for detecting inactive ALDH2 were 78.9 and 82.1%, respectively. Interestingly, drinking ≥7 units/wk in men or ≥3.5 units/wk in women significantly increased the risk of benign gastric ulcer (BGU) among positive alcohol flushers (odds ratio, 8.97; 95% confidence interval, 1.38 to 58.30), but not among negative alcohol flushers. CONCLUSIONS: Simple flushing questionnaires may be administered to the Korean population as a screening tool in detecting individuals who carry inactive ALDH2. Alcohol flushing response negatively correlates with drinking problems and can modify the risk for BGU by alcohol intake.

MANAGEMENT OF ENDOCRINE DISEASE: Flushing: current concepts.

OBJECTIVE: Flushing can be defined as a sensation of warmth accompanied by erythema that most commonly is seen on the face and which occurs in episodic attacks. Such a problem can be clinically problematic, since many conditions and drugs can be related to flushing, and while often there appears to be no underlying organic disease, it is important to exclude disorders since they may be life-threatening conditions. DESIGN AND METHODS: We performed a search in MEDLINE using the terms 'flushing' in combination with 'carcinoid syndrome', 'pheochromocytoma', 'mastocytosis', 'menopausal hot flush' and 'treatment'. European and American guidelines relating to neuroendocrine tumours, mastocytosis and menopause were reviewed. RESULTS: In this review, we discuss the main causes of flushing and propose an algorithm based on pathogenesis, which can be used to guide the clinical evaluation process. We also review recent significant developments in the assessment and treatment of the carcinoid syndrome and menopausal hot flushes, which should guide the clinical practice regarding this common but sometimes confusing condition. CONCLUSIONS: When evaluating flushing, a precise systematic approach is needed to exclude potentially serious underlying causes, although despite this, the cause of the disorder is not always found. If symptoms are not progressive, the patient should be advised about its apparently benign nature in order to avoid unnecessary studies or initiating treatments of minimal benefit.

Alcohol consumption and bladder cancer risk with or without the flushing response: The Japan Public Health Center-based Prospective Study.

The association between alcohol consumption and bladder cancer risk has been insufficiently investigated in East Asian populations, who frequently have the inactive enzyme for metabolizing acetaldehyde. Given that acetaldehyde associated with alcohol consumption is assessed as a carcinogen, consideration of differences in acetaldehyde exposure would aid accuracy in assessing the bladder cancer risk associated with alcohol consumption. Here, we conducted a population-based cohort study in Japan to examine this association, including information on the flushing response as a surrogate marker of the capacity of acetaldehyde metabolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariate Cox proportional hazard models. During follow up from 1990 through 2012 for the 95,915 subjects (45,649 men and 50,266 women, aged 40-69 years), 354 men and 110 women were newly diagnosed with bladder cancer. No significant association between alcohol consumption and bladder cancer risk was observed in the overall analysis. Among male flushers, HRs were 1.04 (95% CI 0.70-1.54), 1.67 (1.16-2.42), 1.02 (0.62-1.67) and 0.63 (0.33-1.20) for alcohol consumption of 1-150, 151-300, 301-450, >450 g/week of pure ethanol compared with non-drinkers and occasional drinkers, respectively, indicating an inverted U-shaped association between alcohol consumption and bladder cancer risk. In contrast, no significant association was identified among male non-flushers. The marginally significant interaction between alcohol consumption and the flushing response (p for interaction = 0.083) may support our hypothesis that acetaldehyde derived from alcohol consumption is associated with bladder cancer risk. A prospective study considering polymorphisms of genes involved in acetaldehyde metabolism is warranted.

Facial flushing after alcohol consumption and the risk of cancer: A meta-analysis.

BACKGROUND: The association between facial flushing after alcohol consumption and the risk of cancer remains controversial. The aim of this study was to evaluate the relation between facial flushing and cancer risk. METHODS: PubMed, EMBASE, and Cochrane Library were searched for relevant literature. The patients' baseline characteristics and estimated risks were extracted. Odds ratios (ORs) with 95% confidence intervals (CIs) were pooled to estimate the risk of facial flushing in cancer, and subgroup analysis was performed. RESULTS: Ten studies with 89,376 participants from East Asia were included. The pooled OR of facial flushing in all cancers was 1.43 (95% CI, 1.08-1.91), with the pooled ORs of 1.94 (95% CI, 1.33-2.83) and 0.95 (95% CI, 0.80-1.12) in men and women, respectively. The pooled ORs were also estimated in different cancer types. CONCLUSION: Our results showed that facial flushing response to alcohol was associated with higher cancer risk in men in East Asia, especially in esophageal squamous cell carcinoma, yet facial flushing was not significantly associated with cancer risk among women.

Evaluation of the new ICHD-III beta cluster headache criteria.

AIM: In the revised criteria of the International Classification of Headache Disorders (ICHD-III beta) the following items are added to the diagnostic criteria of cluster headache: ipsilateral sensation of fullness in the ear and ipsilateral forehead/facial flushing. We evaluated the possible additional value of these symptoms for diagnosing cluster headache. METHODS: In this cross-sectional cohort study of (potential) cluster headache patients we investigated these additional symptoms using a Web-based questionnaire. Patients not fulfilling the ICHD-II criteria for cluster headache but fulfilling the ICHD-III beta criteria were interviewed. RESULTS: Response rate was 916/1138 (80.5%). Of all 573 patients with cluster headache according to ICHD-II criteria, 192 (33.5%) reported ipsilateral ear fullness and 113 (19.7%) facial flushing during attacks. There was no difference in reporting ipsilateral ear fullness and facial flushing between patients who received a diagnosis of cluster headache and patients who did not. None of the patients who did not fulfill all ICHD-II criteria could be categorized as cluster headache according to the ICHD-III beta criteria. CONCLUSION: The results of this study do not support the addition of ear fullness and facial flushing to the new ICHD-III beta criteria.

Predictors of Repeat Epinephrine Administration for Emergency Department Patients with Anaphylaxis.

BACKGROUND: Risk factors that predict which patients with anaphylaxis might require repeat doses of epinephrine are poorly understood. OBJECTIVE: The objective of this study was to identify risk factors associated with the need for multiple doses of epinephrine during an anaphylactic reaction. METHODS: Patients were included if they met diagnostic criteria for anaphylaxis on presentation to the emergency department (ED) at our academic medical center between April 2008 and February 2014. Data were collected on allergic history, presenting signs and symptoms, anaphylaxis management, and disposition. Univariable and multivariable analyses were performed to estimate associations between possible risk factors and the need for multiple doses. RESULTS: Of 582 ED patients with anaphylaxis, 45 (8%) required multiple doses of epinephrine. By multivariable analysis, factors associated with the need for repeat doses were a history of anaphylaxis (odds ratio [OR], 2.5 [95% CI, 1.3-4.7]; P = .005), the presence of flushing or diaphoresis (OR, 2.4 [95% CI, 1.3-4.5]; P = .007), and the presence of dyspnea (OR, 2.2 [95% CI, 1.0-5.0]; P = .046). Patients who received more than 1 dose were more likely to be admitted to the general medical floor (OR, 2.8 [95% CI, 1.1-7.2]; P = .03) or intensive care unit (OR, 7.6 [95% CI, 3.7-15.6]; P < .001). CONCLUSION: Patients with a history of anaphylaxis, flushing or diaphoresis, or dyspnea may require multiple doses of epinephrine to treat anaphylactic reactions. Patients who require more than 1 dose are more likely to be admitted to the hospital, thus increasing health care resource utilization.

Immediate-type hypersensitivity reactions due to antituberculosis drugs: a successful readministration protocol.

BACKGROUND: Little is known about drug hypersensitivity reactions from antituberculosis drugs. OBJECTIVE: To determine the frequency, risk factors, and characteristics of immediate-type hypersensitivity reactions from first-line antituberculosis drugs and to evaluate the usefulness of a readministration protocol for culprit drugs in this group of patients. METHODS: The study population consisted of patients with tuberculosis who were hospitalized and treated in the authors' hospital in 2011. Demographics and disease and treatment characteristics of patients with immediate-type hypersensitivity from antituberculosis drugs were compared with the other patients. Culprit drugs were readministered gradually according to a defined protocol to patients with immediate-type hypersensitivity. RESULTS: Tree hundred seventy-nine patients were included in the study. Eighteen immediate-type hypersensitivity reactions were detected in 13 patients (3.43%). The only identified risk factor was female sex (odds ratio 4.085). Isoniazid, rifampicin, pyrazinamide, and ethambutol were readministered in 11 patients and rifampicin was readministered in 2 patients, with 6- to 8-step protocols for each drug. Only in 2 patients did allergic reactions with rifampicin develop during the procedure. In these patients, after treatment and complete remission of allergic symptoms, the last tolerated dose was administered and the protocol was completed with the same adjustments. CONCLUSION: Immediate-type allergic reactions from antituberculosis drugs are not rare and not related to disease or treatment characteristics. The protocols used in this study provide a useful and safe method for readministration of culprit drugs to patients with antituberculosis drug hypersensitivity.

Comparison of the efficacy and safety of once-daily dosing and on-demand use of udenafil for type 2 diabetic patients with erectile dysfunction.

We compared the efficacy and safety between once-daily dosing and on-demand use of udenafil for type 2 diabetic patients with erectile dysfunction (ED). A multi-center, randomized, open-label, parallel-group, 12-week study was conducted. 161 patients who improved with on-demand 200 mg of udenafil according to Sexual Encounter Profile (SEP) diary Question 2 and 3 (Q2 and Q3) were randomized into 200 mg on-demand (n = 80) or 50 mg once-daily (n = 81) dosing groups for 8 weeks. The dosing period was followed by a 4-week treatment-free period. The primary efficacy endpoint was the change of the International Index of Erectile Function (IIEF) erectile function domain (EFD) score. The secondary efficacy endpoints included changes to the SEP diary Q2, Q3, IIEF Q3, Q4, other domains of IIEF, Global Assessment Question, and shift to the normal rate (EFD ≥ 26). Vascular endothelial markers were also assessed. The IIEF-EFD score of both groups improved after 8 weeks of treatment (P < 0.0001). There was no statistically significant difference between two groups. Improvement was not maintained after the treatment-free follow-up period. Similar results were observed in the secondary efficacy endpoints. There was also no significant difference in vascular endothelial markers. Daily udenafil was well-tolerated, and there was no significant difference in the adverse drug reactions and adverse events between the two groups. Flushing and headache were the most frequent adverse events. Both regimens improved ED in diabetic patients and were well-tolerated. Further studies are needed to assess the effect of daily udenafil treatment in diabetic patients.

Red face revisited: Flushing.

The term red face is reserved for lesions located exclusively or very predominantly on the face that result from changes in cutaneous blood flow triggered by multiple different conditions. Facial erythema may not only present clinically as a distinct entity, but can also be a sign of other diseases. Patients with a red face challenge clinicians to consider a broad differential diagnosis. Diagnosis is based on date and mode of appearance, characteristics of the erythema, functional signs, and associated systemic manifestations. In most cases, the cause is a benign disease such as rosacea, contact dermatitis, photodermatosis, and climacterium, and a thorough history and physical examination is enough to make a diagnosis; facial erythema may also present as a symptom of drug allergies, cardiac disease, carcinoid syndrome, pheochromocytoma, mastocytosis, and anaphylaxis, as well as some rare causes such as medullary carcinoma of the thyroid, pancreatic cell tumor, and renal carcinoma where further laboratory, radiologic, or histopathologic studies are required. In this review, the mechanisms of flushing, its clinical differential diagnosis, and management of various conditions that cause flushing are discussed.