Pedro Giavina-Bianchi

Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes

BACKGROUND In recent years, 2 new syndromes of mast cell activation have been described in patients with episodes of mast cell mediator release that range from flushing and abdominal cramping to anaphylaxis: monoclonal mast cell activation syndrome (MMAS) and idiopathic mast cell activation syndrome (MCAS). OBJECTIVE This review will discuss these 2 new syndromes in the larger context of mast cell activation disorders as well as the diagnostic and treatment approaches for these conditions. METHODS PubMed was searched using the following terms: mast cell activation disorder, mast cell activation syndrome, and clonal mast cell. Only English-language articles published up until February 27, 2013, were considered. RESULTS MMAS has been diagnosed in patients with systemic reactions to hymenoptera stings and elevated baseline serum tryptase as well as in patients with unexplained episodes of anaphylaxis. A bone marrow biopsy establishes the diagnosis by revealing the presence of monoclonal mast cells that carry the D816V KIT mutation and/or express CD25 while the diagnostic requirements for systemic mastocytosis are not met. MCAS affects predominantly women in whom no mast cell abnormality or external triggers account for their episodes of mast cell activation. MCAS is a diagnosis of exclusion, and primary and secondary mast cell activation disorders as well as idiopathic anaphylaxis have to be ruled out before making the diagnosis. Patients with MCAS and MMAS are treated in a stepwise fashion with drugs that block the effects of mediators released by mast cells on activation. One third of MCAS patients experience complete resolution of symptoms with treatment, while one third have a major response and one third a minor response to treatment. A combination of drugs is usually necessary to achieve symptom control. No drug trial has been performed in patients with MMAS and MCAS. CONCLUSIONS MMAS and MCAS are 2 newly described, rare syndromes of mast cell activation. Further studies will be necessary to better understand the cause of these conditions and their natural evolution and to validate and improve the treatment approach. Research should also focus on developing drugs with the potential to cure these debilitating disorders. To achieve these goals, centers with expertise in mast cell activation disorders are essential as they allow for a critical mass of these patients to be enrolled in studies while providing those patients with the most up-to-date diagnostic procedures and treatment strategies.

Aerobic training decreases bronchial hyperresponsiveness and systemic inflammation in patients with moderate or severe asthma: a randomised controlled trial

Background The benefits of aerobic training for the main features of asthma, such as bronchial hyperresponsiveness (BHR) and inflammation, are poorly understood. We investigated the effects of aerobic training on BHR (primary outcome), serum inflammatory cytokines (secondary outcome), clinical control and asthma quality of life (Asthma Quality of Life Questionnaire (AQLQ)) (tertiary outcomes). Methods Fifty-eight patients were randomly assigned to either the control group (CG) or the aerobic training group (TG). Patients in the CG (educational programme+breathing exercises (sham)) and the TG (same as the CG+aerobic training) were followed for 3 months. BHR, serum cytokine, clinical control, AQLQ, induced sputum and fractional exhaled nitric oxide (FeNO) were evaluated before and after the intervention. Results After 12 weeks, 43 patients (21 CG/22 TG) completed the study and were analysed. The TG improved in BHR by 1 doubling dose (dd) (95% CI 0.3 to 1.7 dd), and they experienced reduced interleukin 6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1) and improved AQLQ and asthma exacerbation (p<0.05). No effects were seen for IL-5, IL-8, IL-10, sputum cellularity, FeNO or Asthma Control Questionnaire 7 (ACQ-7; p>0.05). A within-group difference was found in the ACQ-6 for patients with non-well-controlled asthma and in sputum eosinophil and FeNO in patients in the TG who had worse airway inflammation. Conclusions Aerobic training reduced BHR and serum proinflammatory cytokines and improved quality of life and asthma exacerbation in patients with moderate or severe asthma. These results suggest that adding exercise as an adjunct therapy to pharmacological treatment could improve the main features of asthma. Trial registration number NCT02033122.

Comorbidities in Severe Asthma: Frequency of Rhinitis, Nasal Polyposis, Gastroesophageal Reflux Disease, Vocal Cord Dysfunction and Bronchiectasis

OBJECTIVES Severe asthma is found in approximately 10% of patients with asthma. Some factors associated with worse asthma control include rhinitis, gastroesophageal reflux disease, vocal cord dysfunction (VCD), nasal polyposis and bronchiectasis. Therefore, we evaluated the prevalence of these illnesses in patients with severe asthma. METHODS We conducted a retrospective analysis of data obtained from electronic medical records of patients with severe asthma between January 2006 and June 2008. Symptoms of rhinitis and gastroesophageal reflux disease were evaluated as well as intolerance to nonsteroidal anti-inflammatory drugs. We evaluated the results of esophagogastroduodenoscopy, videolaryngoscopy and CT scans of the chest in order to confirm gastroesophageal reflux disease, nasal polyposis, vocal cord dysfunction and bronchiectasis. RESULTS We evaluated 245 patients. Rhinitis symptoms were present in 224 patients (91.4%); 18 (7.3%) had intolerance to nonsteroidal anti-inflammatory drugs, and 8 (3.3%) had nasal polyposis. Symptoms of gastroesophageal reflux disease were reported for 173 (70.6%) patients, although the diagnosis of gastroesophageal reflux disease was confirmed based on esophagogastroduodenoscopy or laryngoscopy findings in just 58 (33.6%) patients. Vocal cord dysfunction was suspected in 16 (6.5%) and confirmed through laryngoscopy in 4 (1.6%). The patient records provided CT scans of the chest for 105 patients, and 26 (24.8%) showed bronchiectasis. DISCUSSION Rhinitis and gastroesophageal reflux disease were the most common comorbidities observed, in addition to bronchiectasis. Therefore, in patients with severe asthma, associated diseases should be investigated as the cause of respiratory symptoms and uncontrolled asthma.

Nonsteroidal Anti-Inflammatory Drugs are Major Causes of Drug-Induced Anaphylaxis

BACKGROUND Drugs are responsible for 40% to 60% of anaphylactic reactions treated in the emergency department. A global research agenda to address uncertainties in anaphylaxis includes studies that identify factors associated with morbidity and mortality. OBJECTIVE The present study investigated drug-induced anaphylaxis, etiologies, aggravating factors, and treatment. METHODS A total of 806 patients with adverse drug reactions were screened, and those who had a clinical diagnosis of anaphylaxis were included in the study. Clinical and demographic characteristics of anaphylaxis were described, including etiologies, pathophysiologic mechanisms involved in the reactions, and a personal history of atopy and asthma. Factors associated with disease severity also were identified. RESULTS Anaphylaxis was diagnosed in 117 patients (14.5%). The etiologies were defined in 76% of the cases, nonsteroidal anti-inflammatory drugs being the most frequent. Seventy-eight patients (66.7%) reported a previous reaction to the drug involved in the current reaction or to a drug from the same class and/or group. Epinephrine was used to treat 34.2% of patients who presented with anaphylaxis, and 40.8% of those with anaphylactic reactions with cardiovascular involvement. IgE-mediated reactions were associated with greater severity, manifested by the rates of cardiovascular dysfunction, hospitalization, and use of epinephrine. CONCLUSIONS The prevalence of anaphylaxis is high in patients who seek medical assistance for drug reactions, but its diagnosis is missed in emergency services, and adrenaline is underused. Drugs were prescribed to many patients despite a history of previous reaction. Nonsteroidal anti-inflammatory drugs were implicated in most cases of anaphylaxis induced by drugs, and IgE-mediated reactions were less frequent but more severe.

Allergic asthma in patients with common variable immunodeficiency

To cite this article: Agondi RC, Barros MT, Rizzo LV, Kalil J, Giavina‐Bianchi P. Allergic asthma in patients with common variable immunodeficiency. Allergy 2010; 65: 510–515.

Administration of anti-IgE to a Churg-Strauss syndrome patient.

Background: Treatment of the Churg-Strauss syndrome (CCS) remains a challenge. Many patients relapse after achieving remission, and a substantial proportion of them present adverse drug reactions with relevant morbidity. In most patients, severe asthma and upper respiratory symptoms persist, requiring continuous therapy. The aim of the present study is to describe a patient with CSS who was administered anti-IgE. Case Report: A 46-year-old male patient with CSS followed up for 17 years is described. Upon treatment, CSS showed remission but asthma failed to improve despite high-dose inhaled corticosteroids, long-acting β2-agonists and several courses of systemic steroids. In order to better control asthma, anti-IgE was administered. Following omalizumab administration, asthma symptoms (according to clinical features and lung function tests) and eosinophilia improved. Conclusions: Anti-IgE offers the potential not only to decrease asthma activity but also to reduce the risk of morbidity that can result from currently available treatment options. Whether it can also affect the activity of other CSS components is an open question. As far as we know, there are no published reports about the prescription of omalizumab to patients with CSS and with non-allergic asthma. Anti-IgE improved our patient’s asthma and decreased the eosinophil blood count but did not worsen the outcome of CSS. However, large and long-term studies are necessary before a more widespread utilization of anti-IgE in CSS patients can be implemented.

Occupational Respiratory Allergic Disease Induced by Passiflora alata and Rhamnus purshiana

BACKGROUND There has been an increase in the incidence of occupational asthma along with better understanding of its pathophysiologic mechanisms and etiologic factors. There are no reports of patients with asthma and rhinitis to Passiflora alata (passion flower) and Rhamnus purshiana (cascara sagrada). METHODS We describe two substances of plant origin as causal agents of occupational allergic respiratory diseases in a patient who worked in a pharmacy devoted to the manual preparation of products. RESULTS Skin testing and Western blot confirmed the sensitization of the patient to these plant extracts in vivo and in vitro, respectively. Bronchial challenge confirmed the cause-effect relationship between the allergen exposure and the diseases. CONCLUSIONS We conclude that Passiflora and cascara sagrada are two new etiologic agents of IgE-mediated occupational asthma and rhinitis. The present study also serves to alert physicians to the risks associated with work in pharmacies devoted to manual preparation of plant extracts, emphasizing the importance of the use of protective measures in these environments.

United airway disease: current perspectives

Upper and lower airways are considered a unified morphological and functional unit, and the connection existing between them has been observed for many years, both in health and in disease. There is strong epidemiologic, pathophysiologic, and clinical evidence supporting an integrated view of rhinitis and asthma: united airway disease in the present review. The term “united airway disease” is opportune, because rhinitis and asthma are chronic inflammatory diseases of the upper and lower airways, which can be induced by allergic or nonallergic reproducible mechanisms, and present several phenotypes. Management of rhinitis and asthma must be jointly carried out, leading to better control of both diseases, and the lessons of the Allergic Rhinitis and Its Impact on Asthma initiative cannot be forgotten.

Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions

BACKGROUND The optimal approach to patients with hypersensitivity reactions (HSRs) to taxanes has not been established. OBJECTIVE We sought to assess the safety and efficacy of risk stratification based on the severity of the initial HSR and skin testing for guiding taxane reintroduction in patients with an HSR to these agents. METHODS Data on 164 patients treated for a taxane-related HSR from April 2011 to August 2014 at the Dana-Farber Cancer Institute and Brigham and Womens Hospital were collected retrospectively. Patients were re-exposed to taxanes either through desensitization, challenge, or regular infusion based on the severity of the initial HSR and skin test response. Depending on the initial risk stratification and tolerance to re-exposure, patients were then treated with shorter desensitization protocols, challenge, or both with the aim of resuming regular infusions, except in patients with a severe immediate initial HSR. RESULTS Of 138 patients desensitized, 29 (21%) had an immediate and 20 (14%) had a delayed HSR with the procedure. Of 49 patients challenged, 2 (4%) had a mild immediate and 1 (2%) had a delayed HSR with the procedure. No patients had a severe immediate HSR with desensitization or challenge. Thirty-six (22%) patients eventually resumed regular infusions. These patients were more likely to have negative skin test responses and to have experienced a delayed or mild immediate initial HSR. CONCLUSIONS Risk stratification based on the severity of the initial HSR and skin testing to guide taxane reintroduction is safe and allows a significant number of patients to resume regular infusions.

Outcomes and safety of drug provocation tests.

Drug provocation tests (DPTs) are considered the gold standard for identifying adverse drug reactions (ADRs). The aim of this study was to analyze DPT results and discuss severe systemic reactions associated with them. This was a retrospective analysis of 500 patients with ADRs who sought treatment and were submitted to DPTs when indicated between 2006 and 2010. We performed DPTs according to the European Network for Drug Allergy recommendations. Single-blind, placebo-controlled DPTs were performed with antibiotics, local anesthetics, and nonsteroidal anti-inflammatory drugs, as well as with other drugs. Patient characteristics, DPT results, and reactions were analyzed. The sample comprised 198 patients (80.8% of whom were female patients) submitted to 243 DPTs. Ages ranged from 9 to 84 years (mean, 39.9 years). The 243 DPTs were performed with local anesthetics (n = 93), antibiotics (n = 19), acetaminophen (n = 44), benzydamine (n = 33), COX-2 inhibitors (n = 26), dipyrone (n = 7), aspirin (n = 4), or other drugs (n = 17). The results of 4 tests (1.6%) were inconclusive, whereas those of 10 (4.1%) revealed positive reactions to antibiotics (2/19), COX-2 inhibitors (2/26), acetaminophen (3/44), and local anesthetics (3/93). Two severe reactions were observed: cephalexin-induced anaphylactic shock and bupivacaine-induced anaphylaxis without shock. Four patients (2.0%) reacted to the placebo before administration of the drug. Drug provocation tests are safe for use in clinical practice but they should be placebo-controlled and should be performed under the supervision of an allergist. To confirm a presumptive diagnosis and to manage allergies appropriately, it is crucial to perform DPTs.