Challenges in Drug and Hymenoptera Venom Hypersensitivity Diagnosis and Management in Mastocytosis.

Mastocytosis is a myeloproliferative neoplasm characterized by abnormal proliferation and activation of clonal mast cells typically bearing the KITD816V mutation. Symptoms manifest due to the release of bioactive mediators and the tissue infiltration by neoplastic mast cells. Mast cell activation symptoms include flushing, pruritus, urticaria, abdominal cramping, diarrhea, wheezing, neuropsychiatric symptoms, and anaphylaxis. Up to 50% of patients with mastocytosis report a history of provoked and unprovoked anaphylaxis, with Hymenoptera venom and drugs the most common culprits. NSAIDs, antibiotics, vaccines, perioperative medications, and radiocontrast media are often empirically avoided without evidence of reactions, depriving patients of needed medications and placing them at risk for unfavorable outcomes. The purpose of this review is to highlight the most common agents responsible for adverse drug reactions in patients with mastocytosis, with a review of current epidemiology, diagnosis, and management of drug hypersensitivity and Hymenoptera venom allergy.

Drug and Venom Allergy in Mastocytosis.

Patients with mastocytosis have an increased risk for mast cell activation events including anaphylaxis when exposed to certain drugs and Hymenoptera venom. Hypotension and cardiovascular collapse without skin or other systemic manifestations can occur after Hymenoptera stings, during the perioperative period, and after exposure to nonsteroidal ntiinflammatory drugs, opioids, and other mast cell activating medications, including vancomycin and quinolones. This chapter reviews the epidemiology, mechanisms, diagnosis, management, and treatment options for Hymenoptera venom and drug-induced reactions in patients with mastocytosis.

The Long Road of Long COVID: Specific Considerations for the Allergist/Immunologist.

Long COVID (coronavirus disease 2019) syndrome, also known as post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a new disorder that can develop after an acute infection with the SARS-CoV-2 virus. The condition is characterized by multiorgan system involvement with a wide range of symptoms that can vary in severity from mild to debilitating. Some of the common symptoms associated with long COVID syndrome include cardiovascular issues such as heart palpitations and chest pain; thrombotic events (eg, blood clotting disorders); metabolic problems (eg, type 2 diabetes); dysautonomia; paroxysmal orthostatic tachycardia syndrome; myalgic encephalomyelitis/chronic fatigue syndrome; reactivation of the Epstein-Barr virus; the presence of autoantibodies; chronic spontaneous urticaria (hives); and connective tissue diseases. Whereas long COVID syndrome can affect individuals from various backgrounds, certain populations may be at higher risk such as individuals of Hispanic and Latino heritage, as well as those with low socioeconomic status, although approximately one-third of affected patients have no known risk factors or preexisting conditions. Many survivors of COVID-19 struggle with multiple symptoms, increased disability, reduced function, and poor quality of life. Whereas vaccination has been the most significant intervention able to decrease the severity of acute SARS-Cov2 infection and curtail deaths, limited data are available related to its modulating effect on long COVID necessitating the need for further investigation. Furthermore, several inflammatory pathways have been proposed for the pathogenesis of long COVID that are the targets for ongoing clinical studies evaluating novel pharmacological agents. The purpose of the present report is to review the many factors associated with long COVID with a focus on those aspects that have relevance to the allergist-immunologist.

Anaphylaxis and systemic mastocytosis caused by Solenopsis invicta stings / Anafilaxia e mastocitose sistêmica ocasionada pela Solenopsis invicta

Indolent systemic mastocytosis is a rare disease characterized by an increased number of mast cells in the bone marrow and other tissues, such as the liver, spleen, lymph nodes, and skin. Patients with indolent systemic mastocytosis and high serum tryptase levels are at risk for Hymenoptera venom-induced anaphylaxis. Hymenoptera venom immunotherapy in patients with specific IgE is safe and effective. While some patients can receive ultra-rush venom immunotherapy with minimal side effects, omalizumab effectively protects against anaphylaxis during the build-up phase.

A mastocitose sistêmica indolente é uma doença rara caracterizada por um número aumentado de mastócitos na medula óssea e em outros tecidos, como fígado, baço, linfonodos e pele. Pacientes com mastocitose sistêmica indolente e altos níveis séricos de triptase correm risco de anafilaxia induzida pelo veneno dos Hymenoptera. A imunoterapia com veneno de himenópteros em pacientes com IgE específica é segura e eficaz. Embora alguns pacientes possam receber imunoterapia com veneno ultrarrápido com efeitos colaterais mínimos, o omalizumabe protegeu efetivamente contra a anafilaxia durante a fase de acúmulo.

Utilizing Biologics in Drug Desensitization.

PURPOSE OF REVIEW: The purpose of this literature review was to review the latest advancements with biologics in rapid drug desensitization. Our methodology was to highlight both desensitization to biologics themselves and the use of biologics in desensitization to both biologic and nonbiologic drugs. RECENT FINDINGS: Biologics are a vast category of drugs that include monoclonal antibodies, nanobodies, modern vaccinations, and even hormones. Desensitization to biologics can be safely performed through standardized procedure. Biomarkers are used both in vitro and in vivo to help identify and classify hypersensitivity reactions. Hypersensitivity reactions to the mRNA vaccinations against SARS-CoV-2 present their own unique challenges to management. There are specific excipients in monoclonal antibodies that are thought to be responsible for many of their hypersensitivity reactions. Certain biologics can even be used to assist in desensitization to other drugs. Rapid drug desensitization is a standardized procedure that may be able to help many patients who have experienced hypersensitivity reactions to biologics and would best be treated with them to continue to receive them. Biologic drugs have opened a new era in medicine for the prevention and treatment of infectious diseases, cancer, and inflammatory diseases. Hypersensitivity reactions to biologics are quite common. This literature review presents the latest advancements in our understanding of hypersensitivity reactions to biologics, how rapid drug desensitization can be used to continue therapy despite history of hypersensitivity, and how biologics themselves can be used to aid in desensitization itself.

Basophil Activation Test as a Biomarker for Taxanes Anaphylaxis.

Introduction: Taxanes are widely used chemotherapy agents, and their administration, despite premedication, is associated with hypersensitivity reactions (HR) in up to 9% of patients, 1% of which are severe. The mechanisms of these reactions are not fully understood. Finding biomarkers for early diagnosis and better understanding the underlying mechanisms of these reactions are key to defining the best treatment strategy for patients. Methods: The purpose of this study was to evaluate the effectiveness of the basophil activation test (BAT) to diagnose patients with anaphylactic reactions to taxanes. Patients with anaphylaxis to taxane compounds (n = 15) were assessed through clinical history, skin testing (when possible), and BAT. BAT was performed immediately before rapid drug desensitization or before skin testing using anti-CD123 conjugated (APC-Biolegend), anti-HLADR conjugated (FITC-Biolegend) to gate Basophils and anti-CD63 conjugated (PE-Biolegend), and anti-CD203c conjugated (BV-Biolegend) to assess CD203c and CD63 expression on basophils under taxane stimulation. BAT was also performed in eight healthy volunteers. Results: BAT was positive for CD203c in eight out of 15 patients and for CD63 in four out of 15 patients and in two out of eight controls. The sensitivity for CD203c was 53%, the specificity was 87%, and the area under the curve was 0.66 (p = 0.19%). For CD63, these rates were 33%, 87%, and 0.6 (p = 0.4). In a subgroup analysis of patients with positive skin tests (11 patients), CD203c was positive in six patients (sensitivity of 54.5% and specificity of 87.5%), and CD63 was positive in five patients (sensitivity of 45% and specificity of 75%). Conclusions: BAT as a diagnostic tool for immediate hypersensitivity reactions to taxanes may be relevant in patients with selected phenotypes and endotypes, especially those with severe reactions or when the diagnosis cannot be established by the skin test. Increased expression of CD203c was more frequent than of CD63 in patients with positive results, and the sensitivity of this biomarker was higher in patient sub-group with positive skin tests, i.e., patients with IgE-mediated endotypes.

Perceptions of patient disease burden and management approaches in systemic mastocytosis: Results of the TouchStone Healthcare Provider Survey.

BACKGROUND: Systemic mastocytosis (SM) is a rare clonal neoplasm driven by the KIT D816V mutation and has a broad range of debilitating symptoms. In this study, the authors evaluated SM disease perceptions and management strategies among US health care providers (HCPs). METHODS: Hematologist/oncologist (H/O) HCPs and allergist/immunologist (A/I) HCPs who were treating four or more patients with SM completed an online, 51-item TouchStone HCP Survey, which queried provider characteristics, perceptions of disease burden, and current management. Descriptive analyses by specialty and SM subtype were performed. RESULTS: Of 304 HCPs contacted, 111 (37%) met eligibility criteria, including 51% A/I specialists and 49% H/O specialists. On average, the HCPs had 14 years of practice experience and cared for 20 patients with SM. A/I HCPs saw more patients with nonadvanced SM (78%) compared with H/O HCPs, who saw similar proportions of patients with nonadvanced SM (54%) and advanced SM (46%). HCPs reported testing 75% of patients for the KIT D816V mutation and found an estimated prevalence of 47%. On average, HCPs estimated 8 months between symptom onset and SM diagnosis. HCPs reported that 62% of patients with indolent SM felt depressed or discouraged because of symptoms. In terms of treatment goals for SM, both types of specialists prioritized symptom improvement for nonadvanced SM and improved survival for advanced SM while also prioritizing improving patient quality of life. CONCLUSIONS: Both A/I and H/O specialists highlighted unmet needs for patients with SM. The HCPs surveyed reported a lower rate of KIT D816V mutations and a perceived shorter time between symptom onset and SM diagnosis compared with published estimates. LAY SUMMARY: Specialists treating systemic mastocytosis (SM) completed a 51-item questionnaire about their clinical practices and perceptions of disease impact. The study included 111 hematology, oncology, allergy, and immunology physicians. Physicians reported that most patients had nonadvanced disease, yet SM symptoms significantly disrupted their patients' lives. Physicians estimated that SM is diagnosed within months of symptom onset, in contrast with published reports of years' long delays reported by patients with SM. This study identified unmet needs that can inform educational and patient management priorities in this rare disease.

Patient-reported outcomes among patients with systemic mastocytosis in routine clinical practice: Results of the TouchStone SM Patient Survey.

BACKGROUND: Systemic mastocytosis (SM) is a rare clonal neoplasm driven by KIT D816V and other mutations. Data were collected from the patient perspective on disease burden and included an SM-specific symptom assessment tool. METHODS: US adults aged 18 years and older with a self-reported SM diagnosis completed an online TouchStone SM Patient Survey of 100 items, including the 12-item Short-Form Health Survey, the Indolent Systemic Mastocytosis Symptom Assessment Form, and the Work Productivity and Activity Impairment Questionnaire, as well as questions about SM diagnosis, the impact of SM on daily activities, work impairment, and health care use. The results were analyzed using descriptive statistics. RESULTS: Fifty-six individuals completed the survey (89% women; median age, 48 years; mean time since diagnosis, 6.7 years), reporting indolent SM (66%), aggressive SM (9%), smoldering SM (5%), and unknown SM subtype (18%). Over a 1-year recall, respondents reported seeking emergency care for anaphylaxis (30%) and taking three or more prescription medications (52%) for SM. Over one half of patients (54%) reduced their work hours because of SM, and 64% avoided leaving home because of symptoms. A majority of respondents (93%) had experienced ≥10 SM-related symptoms, noting that the most bothersome were anaphylactic episodes (18%), abdominal/stomach pain (16%), diarrhea/loose stools (13%), and fatigue (11%). Whereas an Indolent Systemic Mastocytosis Symptom Assessment Form-derived total symptom score of 28 is used to indicate moderate-to-severe symptoms, the mean total symptom score was 52.7. Mental and physical component summary scores from the 12-item Short-Form Health Survey were below population norms. CONCLUSIONS: Patients who were surveyed reported substantial symptom burden and unmet needs because of SM, as evidenced by seeking emergency care and reporting bothersome symptoms, poor quality of life, and reduced work hours and productivity. LAY SUMMARY: The objective of this research was to understand the burden and unmet needs in the rare disease of systemic mastocytosis (SM) to guide future care. Fifty-six patients completed an online survey containing questions about their diagnosis, medications, health care use, quality of life, and SM symptoms. The results demonstrated that SM is associated with severe and burdensome symptoms, anaphylactic events, emergency department visits, use of multiple medications, reduced ability to work, and poor physical and psychological quality of life. These findings suggest the need for future advances to address unmet needs in patients affected by SM.

The Who, What, Where, When, Why, and How of Drug Desensitization.

Hypersensitivity reactions to drugs have increased in the past 25 years due to increased exposures and availability of efficient, targeted, and personalized medications. Rapid drug desensitization is a clinical procedure that allows for the safe administration of a drug in patients with a history of such hypersensitivity reactions. Desensitization allows the continued use of first-line therapies, leading to higher efficacy of treatment, fewer side effects, cost-effectiveness, and increased quality of life and life expectancy of patients when compared with the use of second-line therapy. In this review, we discuss the who, what, where, when, why, and how of drug desensitization.

The Magnification of Health Disparities During the COVID-19 Pandemic.

Coronavirus disease 2019 has created and amplified racial health disparities. This has been particularly noticeable in populations with asthma. There is no one simple reason for this occurrence, but rather a complex interaction of biological, structural, and socioeconomic factors. This article will highlight reasons why the coronavirus disease 2019 pandemic has been particularly impactful among minority populations throughout the world and will also offer potential solutions to help overcome health disparities.

Hypersensitivity Reactions to Platinum Agents and Taxanes.

Hypersensitivity reactions (HSRs) to chemotherapy agents can present a serious challenge to treating patients with preferred or first-line therapies. Allergic reactions through an immunologic mechanism have been established for platinum and taxane agents, which are used to treat a wide variety of cancers including gynecologic cancers. Platin HSRs typically occur after multiple cycles of chemotherapy, reflecting the development of drug IgE sensitization, while taxane HSRs often occur on first or second exposure. Despite observed differences between platin and taxane HSRs, drug desensitization has been an effective method to reintroduce both chemotherapeutic agents safely. Skin testing is the primary diagnostic tool used to risk-stratify patients after initial HSRs, with more widespread use for platinum agents than taxanes. Different practices exist around the use of skin testing, drug challenge, and choice of desensitization protocol. Here, we review the epidemiology, mechanism, and clinical presentation of HSRs to platinum and taxane agents, as well as key controversies in their evaluation and management.

Anaphylaxis and Pregnancy: A Systematic Review and Call for Public Health Actions.

BACKGROUND: Although rare, anaphylaxis during pregnancy implies a risk to both mothers and newborns. OBJECTIVE: This systematic review is intended to identify key issues in the diagnosis and management of this condition to support prevention strategies and decrease the risk for death related to anaphylaxis during pregnancy. METHODS: We searched MEDLINE, Cochrane, LILACS, SciELO, and Science Direct databases for manuscripts concerning the term "anaphylaxis during pregnancy," without language restrictions. We screened studies, extracted data, and assessed the risk for bias independently in duplicate. RESULTS: We selected 12 articles. Frequency of anaphylaxis during maternity was estimated to be 1.5 to 3.8 per 100,000 pregnancies. Only one study provided anaphylaxis mortality data in pregnant women; the rate of anaphylaxis-related maternal mortality was estimated at 0.05/100,000 live births. No standard definition of anaphylaxis severity has been used. A total of 49% to 74% of anaphylaxis cases were described during caesarean section. Beta-lactam antibiotics (58%), latex (25%), and anesthetic agents (17%) were the main causes. In 17% of reports, causative agents were proven by allergy testing. Moreover, 72% of articles proposed the same management and treatment for a clinical episode of anaphylaxis during pregnancy as for nonpregnant patients, and the use of epinephrine in the patient's care during anaphylaxis in pregnancy. CONCLUSIONS: Few studies address anaphylaxis during pregnancy. Most have been produced by nonallergy specialists. Collaboration among different specialists involved in the care of pregnant women should be established to support preventive strategies and reduce avoidable deaths.

Drug Desensitizations for Chemotherapy: Safety and Efficacy in Preventing Anaphylaxis.

Hypersensitivity reactions (HSRs) to antineoplastic drugs are increasing due to the expanding use of classical and new drugs in a wide variety of malignancies. PURPOSE OF REVIEW: The goal of this review is to provide current best practices in the diagnosis and management of HSRs based on data and evidence. RECENT FINDINGS: A plethora of studies have provided evidence of the safety and efficacy of rapid drug desensitizations (RDD) to allow for the reintroduction of antineoplastic drugs following an HSR, based on risk stratification. Recently described biomarkers such as basophil activation test, total IgE, BRCA genotyping, and serum IL-6 can aid in guiding improved precision desensitization protocols. Personalized premedication regimens and protocols have improved RDD safety and outcomes. RDD allows for the continued use of chemotherapeutic drugs without impaired drug efficacy. RDD represents the best approach to maintain cancer patients on their most effective treatments.

Mast Cell Activation During Suspected Perioperative Hypersensitivity: A Need for Paired Samples Analysis.

BACKGROUND: Perioperative hypersensitivity (POH) reactions constitute a significant clinical and diagnostic challenge. A transient increase in serum tryptase during POH reflects mast cell activation (MCA) and helps to recognize an underlying hypersensitivity mechanism. OBJECTIVE: To determine the diagnostic performance of different tryptase decision thresholds based on single and paired measurements to document MCA in suspected POH. METHODS: Acute serum tryptase (aST) and baseline serum tryptase (bST) samples were obtained from patients referred to our outpatients clinic because of clinical POH. Tryptase samples from controls were obtained before induction (Tt0) and 1.5 hours after induction (Tt1) in uneventful anesthesia. Different cutoff points for tryptase increase over bST and the percentage increase in tryptase (%T) were calculated and compared with existing thresholds: aST > [1.2 × (bST) + 2] (consensus formula), aST higher than 11.4 ng/mL, and aST higher than 14 ng/mL. RESULTS: Patients with POH had higher bST and aST levels compared with controls (respectively 5.15 vs 2.28 ng/mL for bST and 20.30 vs 1.92 ng/mL for aST). The consensus formula and a tryptase increase over bST of greater than or equal to 3.2 ng/mL held the highest accuracies to document MCA in POH (respectively 81% and 82%). A bST of higher than 8 ng/mL was present in 4% of controls, 5% of patients with grade 1 POH, 24% of patients with grade 2 POH, 15% of patients with grade 3 POH, and 17% of patients with grade 4 POH. CONCLUSIONS: Our data endorse the consensus formula for detection of MCA in POH. Furthermore, it shows that a bST of higher than 8 ng/mL was associated with occurrence of anaphylaxis.

Use and Interpretation of Acute and Baseline Tryptase in Perioperative Hypersensitivity and Anaphylaxis.

Paired acute and baseline serum or plasma tryptase sampling and determination have recently been included as a mechanistic approach in the diagnostic and management guidelines of perioperative immediate hypersensitivity and anaphylaxis. The timing of this paired sampling is clearly defined in international consensus statements, with the optimal window for acute tryptase sampling between 30 minutes and 2 hours after the initiation of symptoms, whereas baseline tryptase should be measured in a sample collected before the event (preop) or at least 24 hours after all signs and symptoms have resolved. A transient elevation of the acute tryptase level greater than [2 + (1.2 × baseline tryptase level)] supports the involvement and activation of mast cells. Here, we provide the clinical, pathophysiological, and technical rationale for the procedure and interpretation of paired acute and baseline tryptase. Clinical examples, up-to-date knowledge of hereditary α-tryptasemia as a frequent cause of baseline tryptase of 7 µg/L and higher, mastocytosis, other clonal myeloid disorders, cardiovascular or renal failure, and technical improvements resulting in continued lowering of the 95th percentile value are discussed. Clues for improved management of perioperative immediate hypersensitivity and anaphylaxis include (1) sustained dissemination and implementation of updated guidelines; (2) preoperative sample storage for deferred analysis; (3) referral for thorough allergy investigation, screening for mast cell-related disorders, and recommendations for future anesthetic procedures; and (4) sustained collaboration between anesthesiologists, immunologists, and allergists.