Alergia a la leche de vaca: ¿se pueden evitar las pruebas de provocación oral? Un análisis probabilístico basado en datos clínicos / Cow's milk allergy: Can oral food challenges be avoided? A probabilistic analysis based on clinical data

Introducción. La prueba de provocación oral (PPO) para el diagnóstico de alergia a las proteínas de la leche de la vaca (APLV) presenta riesgos y requiere de recursos. Nuestro objetivo fue evaluar condiciones y pruebas complementarias para identificar una alta probabilidad de APLV. Población y métodos. Análisis secundario sobre estudio de pacientes atendidos en una unidad de alergia entre 2015 y 2018. Se determinaron las probabilidades prepruebas asociadas a los síntomas y sus combinaciones, y las probabilidades pospruebas luego de realizadas pruebas cutáneas y determinación de inmunoglobulina E (IgE) sérica. Resultados. Se evaluó la información de 239 pacientes. Se observaron probabilidades mayores al 95 % en pacientes con angioedema y combinación de urticaria y vómitos. Usando puntos de corte propuestos por Calvani et al., la combinación de vómitos con rinitis, sin angioedema, también superó el 95 %. Conclusión. Se ofrece una metodología para identificar pacientes en los que puede diagnosticarse APLV sin realización de PPO.

Introduction. The oral food challenge (OFC) for the diagnosis of cow's milk protein allergy (CMPA) poses risks and requires resources. Our objective was to assess conditions and complementary tests used to identify a high probability of CMPA. Population and methods. Secondary analysis of a study of patients seen at a unit of allergy between 2015 and 2018. Pre-testing probabilities associated with symptoms and their combinations and post-testing probabilities after skin prick testing and serum immunoglobulin E (IgE) levels were determined. Results. The data from 239 patients were assessed. A probability greater than 95% was observed for angioedema and a combination of urticaria and vomiting. Based on the cut-off points proposed by Calvani et al., the combination of vomiting with rhinitis, without angioedema, also exceeded 95%. Conclusion. A methodology is provided to identify patients in whom CMPA may be diagnosed without an OFC.

Patients With Chronic Spontaneous Urticaria Who Have Wheals, Angioedema, or Both, Differ Demographically, Clinically, and in Response to Treatment-Results From CURE.

BACKGROUND: Patients with chronic spontaneous urticaria (CSU) have spontaneous wheals (W), angioedema (AE), or both, for longer than 6 weeks. Clinical differences between patients with standalone W, standalone AE, and W and AE (W+AE) remain incompletely understood. OBJECTIVE: To compare W, AE, and W+AE CSU patients regarding demographics, disease characteristics, comorbidities, disease burden, and treatment response. METHODS: Baseline data from 3,698 CSU patients in the ongoing, prospective, international, multicenter, observational Chronic Urticaria REgistry (CURE) were analyzed (data cut: September 2022). RESULTS: Across all CSU patients, 59%, 36%, and 5% had W+AE, W, and AE, respectively. The W+AE patients, compared with W and AE patients, showed the lowest male-to-female ratio (0.33), higher rates of concomitant psychiatric disease (17% vs 11% vs 6%, respectively), autoimmune disease (13% vs 7% vs 9%, respectively), and nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (9% vs 5% vs 2%, respectively) and the highest disease impact. The W patients, compared with W+AE and AE patients, showed the lowest rates of concomitant hypertension (15% vs 21% vs 40%, respectively) and obesity (11% vs 16% vs 17%, respectively), the highest rate of concomitant inducible urticaria (24% vs 22% vs 6%, respectively), and shorter W duration. The AE patients, compared with W+AE and W patients, were older at disease onset, showed longer AE duration, and the best response to increased doses of H1-antihistamines (58% vs 24% vs 31%, respectively) and omalizumab (92% vs 67% vs 60%, respectively). CONCLUSIONS: Our findings provide a better understanding of CSU phenotypes and may guide patient care and research efforts that aim to link them to pathogenic drivers.

How Infection and Vaccination Are Linked to Acute and Chronic Urticaria: A Special Focus on COVID-19.

Since more than a century ago, there has been awareness of the connection between viral infections and the onset and exacerbation of urticaria. Our knowledge about the role of viral infection and vaccination in acute and chronic urticaria improved as a result of the COVID-19 pandemic but it has also highlighted knowledge gaps. Viral infections, especially respiratory tract infections like COVID-19, can trigger the onset of acute urticaria (AU) and the exacerbation of chronic urticaria (CU). Less frequently, vaccination against viruses including SARS-CoV-2 can also lead to new onset urticaria as well as worsening of CU in minority. Here, with a particular focus on COVID-19, we review what is known about the role of viral infections and vaccinations as triggers and causes of acute and chronic urticaria. We also discuss possible mechanistic pathways and outline the unmet needs in our knowledge. Although the underlying mechanisms are not clearly understood, it is believed that viral signals, medications, and stress can activate skin mast cells (MCs). Further studies are needed to fully understand the relevance of viral infections and vaccinations in acute and chronic urticaria and to better clarify causal pathways.

Cow's milk allergy: Can oral food challenges be avoided? A probabilistic analysis based on clinical data. / Alergia a la leche de vaca: ¿se pueden evitar las pruebas de provocación oral? Un análisis probabilístico basado en datos clínicos.

Introduction. The oral food challenge (OFC) for the diagnosis of cow's milk protein allergy (CMPA) poses risks and requires resources. Our objective was to assess conditions and complementary tests used to identify a high probability of CMPA. Population and methods. Secondary analysis of a study of patients seen at a unit of allergy between 2015 and 2018. Pre-testing probabilities associated with symptoms and their combinations and post-testing probabilities after skin prick testing and serum immunoglobulin E (IgE) levels were determined. Results. The data from 239 patients were assessed. A probability greater than 95% was observed for angioedema and a combination of urticaria and vomiting. Based on the cut-off points proposed by Calvani et al., the combination of vomiting with rhinitis, without angioedema, also exceeded 95%. Conclusion. A methodology is provided to identify patients in whom CMPA may be diagnosed without an OFC.

Introducción. La prueba de provocación oral (PPO) para el diagnóstico de alergia a las proteínas de la leche de la vaca (APLV) presenta riesgos y requiere de recursos. Nuestro objetivo fue evaluar condiciones y pruebas complementarias para identificar una alta probabilidad de APLV. Población y métodos. Análisis secundario sobre estudio de pacientes atendidos en una unidad de alergia entre 2015 y 2018. Se determinaron las probabilidades prepruebas asociadas a los síntomas y sus combinaciones, y las probabilidades pospruebas luego de realizadas pruebas cutáneas y determinación de inmunoglobulina E (IgE) sérica. Resultados. Se evaluó la información de 239 pacientes. Se observaron probabilidades mayores al 95 % en pacientes con angioedema y combinación de urticaria y vómitos. Usando puntos de corte propuestos por Calvani et al., la combinación de vómitos con rinitis, sin angioedema, también superó el 95 %. Conclusión. Se ofrece una metodología para identificar pacientes en los que puede diagnosticarse APLV sin realización de PPO.

Documented Adverse Drug Reactions and Discontinuation of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Chronic Kidney Disease.

INTRODUCTION: Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are frequently discontinued in patients with chronic kidney disease (CKD). Documented adverse drug reactions (ADRs) in medical records may provide insight into the reasons for treatment discontinuation. METHODS: In this retrospective cohort of US veterans from 2005 to 2019, we identified individuals with CKD and a current prescription for an ACEi or ARB (current user group) or a discontinued prescription within the preceding 5 years (discontinued group). Documented ADRs in structured datasets associated with an ACEi or ARB were categorized into 17 pre-specified groups. Logistic regression assessed associations of documented ADRs with treatment discontinuation. RESULTS: There were 882,441 (73.0%) individuals in the current user group and 326,794 (27.0%) in the discontinued group. There were 26,434 documented ADRs, with at least one documented ADR in 7,520 (0.9%) current users and 9,569 (2.9%) of the discontinued group. ADR presence was associated with treatment discontinuation, aOR 4.16 (95% CI: 4.03, 4.29). The most common documented ADRs were cough (37.3%), angioedema (14.2%), and allergic reaction (10.4%). ADRs related to angioedema (aOR 3.81, 95% CI: 3.47, 4.17), hyperkalemia (aOR 2.03, 95% CI: 1.84, 2.24), peripheral edema (aOR 1.53, 95% CI: 1.33, 1.77), or acute kidney injury (aOR 1.32, 95% CI: 1.15, 1.51) were associated with treatment discontinuation. CONCLUSION: ADRs leading to drug discontinuation were infrequently documented. ADR types were differentially associated with treatment discontinuation. An understanding of which ADRs lead to treatment discontinuation provides an opportunity to address them at a healthcare system level.

Food-Dependent Exercise-Induced Wheals/Angioedema, Anaphylaxis, or Both: A Systematic Review of Phenotypes.

BACKGROUND: Food-dependent exercise-induced allergic reactions can manifest with wheals, angioedema, and anaphylaxis, alone or in combination. OBJECTIVE: To systematically review the clinical manifestation, culprit foods and exercise, augmenting factors, comorbidities, and treatment options of each phenotype. METHODS: Using predefined search terms, we assessed and analyzed the relevant literature until June 2021. Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations were applied to this systematic review. RESULTS: A total of 231 studies with 722 patients were included. The most common phenotype was anaphylaxis with wheals, angioedema, or both, reported in 80% of patients. This was associated with a higher number of anaphylactic episodes, augmenting factors, and use of on-demand antihistamine compared with the least common phenotype, anaphylaxis without wheals or angioedema, reported in 4% of patients. Anaphylaxis with wheals/angioedema was also associated with distinct characteristics compared with stand-alone wheals, angioedema, or both, in 17% of patients. Patients with anaphylaxis were older at the time of disease onset, less often had a history of atopy, showed more positive results in response to food and exercise provocation tests, had a more restricted spectrum of culprit foods, and more often used on-demand epinephrine. CONCLUSIONS: The three phenotypes of allergic reactions to food and exercise differ in clinical characteristics, triggers, and response to treatment. Knowledge of these differences may help with patient education and counseling as well as disease management.

Physical urticaria: Clinical features, pathogenesis, diagnostic work-up, and management.

Physical urticaria is a type of urticaria in which recurrent wheals and/or angioedema occur following exposure of the skin to a physical stimulus. It is classified according to its triggers, which may be mechanical (friction, pressure, and vibration), thermal (cold and heat), or solar electromagnetic radiation. Symptoms of different physical urticarias can develop following specific activities that expose patients to an eliciting stimulus and may be variably accompanied by mucosal involvement and systemic symptoms, including nausea, headache, or even anaphylaxis. Differentiation of physical urticaria from other chronic urticarias requires careful clinical assessment and confirmatory provocation testing, which in turn can inform appropriate management. This clinical review provides an evidence-based summary of the epidemiology, clinical features, pathogenesis, diagnostic work-up, and management of physical urticaria.

Chronic Urticaria in Older Adults: Treatment Considerations.

Chronic urticaria is characterized by recurrent wheals and/or angioedema lasting for more than 6 weeks. Chronic urticaria is an extremely disabling disease limiting daily activities, compromising patient quality of life, and frequently associated with psychiatric comorbidities (depression and/or anxiety). Unfortunately, there are still gaps in the knowledge regarding treatment in special populations, especially in older patients. Indeed, there are no specific recommendations for the management and treatment of chronic urticaria in older people; therefore, recommendations for the general population are used. However, the utilization of some medications may be complicated by potential concerns of comorbidities or polypharmacy. Currently, the diagnostic and therapeutic procedures for chronic urticaria in the older patient are the same as those indicated for other age groups. In particular, there is a limited number of blood chemistry investigations for spontaneous chronic urticaria and specific tests for inducible urticaria. With regard to therapy, second-generation anti-H1 antihistamines are used and, in recalcitrant cases, omalizumab (an anti-IgE monoclonal antibody) and possibly cyclosporine A are additional choices. Nonetheless, it should be underlined that in older patients the differential diagnosis can be more difficult, owing to the lower frequency of chronic urticaria and the likelihood of other pathologies that are peculiar for this age group and that can be included in the chronic urticaria differential diagnosis. As far as therapy is concerned, the physiological characteristics of these patients, the possible comorbidities, and the intake of other medications often require a very attentive drug selection for chronic urticaria compared with other age groups. The purpose of this narrative review is to provide an update on the epidemiology, clinical characteristics, and management of chronic urticaria in older patients.

Abnormal T-cell phenotype in episodic angioedema with hypereosinophilia (Gleich syndrome): Frequency, clinical implication, and prognosis.

BACKGROUND: Episodic angioedema with eosinophilia (EAE) (Gleich syndrome) is a rare disorder consisting of recurrent episodes of angioedema, hypereosinophilia, and frequent elevated serum IgM level. METHODS: We conducted a retrospective multicenter nationwide study regarding the clinical spectrum and therapeutic management of patients with EAE in France. RESULTS: A total of 30 patients with a median age at diagnosis of 41 years (range, 5-84) were included. The median duration of each crisis was 5.5 days (range, 1-90), with swelling affecting mainly the face and the upper limbs. Total serum IgM levels were increased in 20 patients (67%). Abnormal T-cell immunophenotypes were detected in 12 patients (40%), of whom 5 (17%) showed evidence of clonal T-cell receptor gamma locus gene (TRG) rearrangement. The median duration of follow-up was 53 months (range, 31-99). The presence of an abnormal T-cell population was the sole factor associated with a shorter time to flare (hazard ratio, 4.15; 95% confidence interval, 1.18-14.66; P = .02). At last follow-up, 3 patients (10%) were able to have all treatments withdrawn and 11 (37%) were in clinical and biologic remission with less than 10 mg of prednisone daily. CONCLUSION: EAE is a heterogeneous condition that encompasses several disease forms. Although patients usually respond well to glucocorticoids, those with evidence of abnormal T-cell phenotype have a shorter time to flare.

The effect of continuing versus withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers on mortality and major adverse cardiovascular events in hypertensive patients undergoing elective non-cardiac surgery: study protocol for a multi-centric open-label randomised controlled trial.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) are commonly prescribed to patients with hypertension. These drugs are cardioprotective in addition to their blood pressure-lowering effects. However, it is debatable whether hypertensive patients who present for non-cardiac surgery should continue or discontinue these drugs preoperatively. Continuing the drugs entails the risk of perioperative refractory hypotension and/or angioneurotic oedema, while discontinuing the drugs entails the risk of rebound hypertension and myocardial ischaemia. The aim of this study is to evaluate the effect of continuation vs withholding of ACEIs/ARBs on mortality and other major outcomes in hypertensive patients undergoing elective non-cardiac surgery. METHODS: The continuing vs withholding of ACEIs/ARBs in patients undergoing non-cardiac surgery is a prospective, multi-centric, open-label randomised controlled trial. Two thousand one hundred hypertensive patients receiving ACEIs/ARBs and planned for elective non-cardiac surgery will be enrolled. They will be randomised to either continue the ACEIs/ARBs including on the day of surgery (group A) or to withhold it 24-36 h before surgery (group B). The primary endpoint will be the difference in the composite outcome of all-cause in-hospital/30-day mortality and major adverse cardiovascular and non-cardiovascular events. Secondary endpoints will be to evaluate the differences in perioperative hypotension, angioneurotic oedema, myocardial injury, ICU and hospital stay. The impact of the continuation vs withholding of the ACEIs/ARBs on the incidence of case cancellation will also be studied. DISCUSSION: The results of this trial should provide sufficient evidence on whether to continue or withhold ACEIs/ARBs before major non-cardiac surgery. TRIAL REGISTRATION: Clinical Trials Registry of India CTRI/2021/01/030199. Registered on 4 January 2021.

Food-Dependent Exercise-Induced Wheals, Angioedema, and Anaphylaxis: A Systematic Review.

BACKGROUND: Food-dependent exercise-induced wheals, angioedema, and anaphylaxis remain insufficiently characterized. OBJECTIVE: We systematically reviewed the literature on clinical manifestations, laboratory investigations, culprit foods, triggering exercise, comorbidities, and treatment outcomes. METHODS: Using predefined search terms and Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) recommendations, we searched 3 electronic databases to identify relevant literature published before July 2021. RESULTS: Of 722 patients (median age 25 years; 55.4% male) from 231 studies (43 cohort studies, 15 cases series, and 173 case reports), 79.6% and 3.7% had anaphylaxis with and without wheals and/or angioedema, respectively. The remaining 16.6% had wheals and/or angioedema without anaphylaxis. The duration from eating to exercising and from exercising to symptom onset ranged from 5 minutes to 6 hours (median 1 hour) and from 5 minutes to 5 hours (median 30 minutes), respectively, and virtually all patients exercised within 4 hours after eating and developed symptoms within 1 hour after exercising. Wheat was the most common culprit food. Running was the most common trigger exercise. Most patients were atopic, and 1 in 3 had a history of urticaria. Aspirin and wheat-based products were the most frequent augmenting factors. On-demand antihistamines, corticosteroids, and epinephrine were commonly used and reported to be effective. Patients who stopped eating culprit foods before exercise no longer developed food-dependent exercise-induced allergic reactions. CONCLUSIONS: Food-dependent exercise-induced allergic reactions are heterogeneous in their clinical manifestations, triggers, and response to treatment. Patients benefit from avoidance of culprit foods before exercise, which highlights the need for allergological diagnostic workup and guidance.

Alpha-Gal Syndrome: A New Etiology for Periorbital Edema.

Alpha-gal syndrome is characterized by an IgE-mediated hypersensitivity response to the carbohydrate galactose-alpha-1,3-galactose. It can manifest as both an immediate drug allergy to pharmaceuticals containing alpha-gal as well as a delayed hypersensitivity response to the ingestion of mammalian meat products. In the United States, sensitization to alpha-gal is thought to occur from tick bites and can cause severe angioedema, most commonly periorbitally and periorally, with high rates of anaphylaxis. We present a unique case of chronic periorbital edema in a carnivorous individual after acquiring a new red meat allergy from Alpha-Gal Syndrome.

The Role of Interleukin 10 and 18 in Chronic Spontaneous Urticaria Pathogenesis in the Context of Angioedema Coexistence.

Chronic spontaneous urticaria (CSU) is defined using clinical symptoms as spontaneous occurrence of itchy wheals and/or angioedema for at least 6 weeks. Angioedema is underdiagnosed in CSU patients, and its presence has significant negative impact on health-related quality of life, daily activities, health care resource utilization, and work. Various cytokines have been found to be involved in pathogenesis of CSU. To study levels of interleukin (IL)-10 and IL-18 in CSU patients and to look for the differences in CSU subgroups divided with regard to angioedema reoccurrence, we included consecutive CSU patients into the study. To assess disease activity, urticaria activity score was used. In addition, we calculated disease duration time. In all groups, Il-10 and Il-18 serum concentrations were measured. The study involved 52 patients with CSU and 47 healthy volunteers. The IL-10 level was statistically significantly higher in patients with CSU compared to the control group. There were no significant differences in level of IL-18 between those groups. Comparison of patients with CSU and angioedema with those without angioedema showed no significant differences in level of IL-10 and IL-18. We see the need for further studies of serum levels of IL-10 and IL-18 to better understand the pathogenesis of the disease and to find markers useful in predicting the symptom type in the course of CSU.

Angioedema with severe acute abdominal pain: Think of hereditary angioedema.

Angioedema can be either mast cell-(histamine-)mediated or bradykinin-mediated. Treatment approaches for the two types are very different, making differential diagnosis critical. Severe acute abdominal pain caused by intestinal angioedema is commonly misdiagnosed, especially when associated with bradykinin-mediated angioedema. After describing a typical clinical scenario and diagnostic journey of a patient with recurrent, undiagnosed abdominal pain due to hereditary angioedema (HAE), a rare variant of bradykinin-mediated angioedema, we delve into the classification and differential diagnosis of the various types of angioedema and provide an overview of appropriate management with an emphasis on the bradykinin-mediated types. Bradykinin-induced angioedema may be inherited or acquired and is infrequent compared to mast cell-mediated angioedema. HAE is a rare disease characterized by recurrent attacks of non-urticarial, nonpruritic edema usually affecting the face, respiratory tract, extremities, gastrointestinal tract, and genitalia. Unlike mast cell-mediated angioedema, painful abdominal symptoms are prevalent in bradykinin-mediated angioedema and are sometimes the only manifestation of an attack, increasing the likelihood of initial misdiagnosis as appendicitis or other forms of acute abdomen. It is important for gastroenterologists to be vigilant for the possibility of angioedema pathology in patients presenting with undiagnosed, recurrent, abdominal symptoms to facilitate accurate diagnosis and effective treatment.

Episodic angioedema with eosinophilia (Gleich's syndrome) associated with urticarial vasculitis: a coincidence or a novel clinical entity?

Episodic angioedema with eosinophilia (EAE) is a rare condition characterized by recurrent attacks of angioedema and urticaria accompanied by a marked elevation of peripheral eosinophil count. We report the case of a young female patient diagnosed with EAE associated with urticarial vasculitis. A 40-year-old female patient was admitted to our institution due to recurrent episodes of cheek and eyelid angioedema in the previous year. Episodes of facial angioedema lasted for two months with spontaneous remission afterwards. In addition, she presented pruritic and painful skin eruptions of erythematous circles, which persisted for longer than 24 h, that were palpable, somewhat purplish, and more pronounced on the face, arms, and trunk. Laboratory investigation showed a sustained elevation of white cell counts with marked eosinophilia. Serum IgM, IgE, and IgA were normal; IgG was slightly elevated. C1-esterase inhibitor and tryptase test were normal. Reverse transcriptase-polymerase chain reaction was performed for detection of FIP1L1-PDGFRA and BCR-ABL rearrangements. None of these alterations were found. Skin biopsies were suggestive of urticarial vasculitis. The patient was submitted to esophagogastroduodenoscopy, which showed mild chronic gastritis, with no eosinophilic infiltration. Cardiac dimensions and function were normal. Abdominal ultrasound and total body CT-scan failed to show lymphadenopathy, organomegaly, and tumors. We report the first case of association between episodic angioedema with eosinophilia and urticarial vasculitis. It is possible that both conditions share a physiopathological mechanism, suggesting that it is not just a chance association.