This review summarizes new research developments and clinical practice recommendations for the diagnosis and management of anaphylaxis presented in the Joint Task Force on Practice Parameters 2023 Anaphylaxis practice parameter Update. It is intended to serve as a high-level summary of the 2023 practice parameter, which makes clinically impactful recommendations based on evidence that has emerged since the 2015 practice parameter. We invite clinicians to explore the full 2023 practice parameter to understand the research methods and underlying evidence that have informed the recommendations summarized here. There are new and evolving diagnostic criteria for anaphylaxis, rules for defining elevated tryptase levels, and recognition of signs and symptoms particular to infants and toddlers. The administration of epinephrine should not be used as a surrogate to diagnose anaphylaxis. Risk factors for anaphylaxis should be assessed on a case-by-case basis. Patient counseling and shared decision-making are essential to support patients\' treatment decisions and capacity to manage the risk of anaphylaxis at home and in other community settings. Activation of emergency medical services after home epinephrine administration may not be required in all cases, and patients should be engaged in shared decision-making to determine when home management may be appropriate.

Mastocytosis is a disease of the mast cells caused by an increase in the number of mast cells due to abnormal proliferation. The disease is associated with a mutation in the c-kit gene, which is a key factor in the development of mast cells. Mastocytosis is classified into two main groups, namely, cutaneous and systemic mastocytosis, based on the site of mast cell accumulation. In cutaneous mastocytosis, the cells purely gather in the skin. In contrast, systemic mastocytosis must affect an internal organ, including the bone marrow, lymph nodes, liver, spleen, and/or the gastrointestinal tract with or without skin involvement. Cutaneous mastocytosis has four distinct presentations, including urticaria pigmentosa, cutaneous mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptive perstans listed from most to least common. This case report presents a rare bullous variant of diffuse cutaneous mastocytosis.

Elevated basal serum tryptase (BST) levels are markers of both mast cell activation and overall mast cell burden. We present a family of four individuals with elevated tryptase levels greater than or equal to 20 mcg/L, all of whom exhibited signs and symptoms suggestive of mast cell activation. Differential diagnoses included hereditary alpha tryptasemia (HaT), systemic mastocytosis (SM), and mast cell activation syndrome (MCAS). In three individuals, SM was ruled out with normal morphology on bone marrow biopsy combined with negative genetic markers. Further workup would be required for the diagnosis of MCAS since serum tryptase levels were not obtained in our emergency department during acute episodes. Although genetic testing for HaT was not available upon initial workup, HaT remains the most likely explanation for this family\'s elevated BST.

Mastocytosis is a rare neoplastic disorder of the mast cell lineage resulting in unregulated proliferation and activation of mast cells. Symptoms worsen in about one-third of pregnant patients. Treatment focuses on management of symptoms with antimediator therapy (H1 & H2 antihistamines, glucocorticoids, and epinephrine, if required). Medication selection requires care during labor and delivery. Although it is generally considered safe to use a medication patient tolerated before, some common medications may need to be avoided or used with caution (eg, codeine, morphine, nonsteroidal antiinflammatory drugs, vancomycin) if the patient does not have any history of exposure to them.

Mast cell activation syndrome (MCAS) is a heterogeneous and rare disorder with episodic and severe activation of mast cells. Because symptoms of mast cell activation are nonspecific, it is important to base the diagnosis on best available clinical and scientific evidence, and not make it one of exclusion. MCAS, much like the mast cell itself, as a whole is greater than the sum of its proposed diagnostic criteria. When each component is considered in isolation, criteria can seem nonspecific, and thus, a broad constellation of symptoms can be attributed to MCAS when they may be due to other disease processes.

In recent years, an association between hypermobile Ehlers-Danlos syndrome (hEDS), mast cell activation syndrome (MCAS), and postural orthostatic tachycardia syndrome (POTS) has garnered attention and patients are increasingly presenting with this triad. However, a real relationship between these entities is unclear due to a lack of scientific validity. We conducted an extensive review of the literature using two different search strategies. A narrower strategy included 88 searches of various combinations of terms for each of the three conditions, yielding 19 unique papers. A broader search included 136 searches of various combinations of terms but included all forms of EDS and yielded 40 unique papers. Of these, only four and nine papers from the narrower and broader search strategies were original research articles. None of these papers resulted from a combination of the search terms for the three conditions. All three clinical entities are controversial in either existence or pathogenesis. MCAS is a poorly defined clinical entity, and many studies do not adhere to the proposed criteria when establishing the diagnosis. Patients previously diagnosed with EDS hypermobility type may not meet the new, stricter criteria for hEDS but may for a less severe hypermobility spectrum disorder (HSD). The pathophysiology of POTS is still unclear. An evidence-based, common pathophysiologic mechanism between any of the two, much less all three conditions, has yet to be described. Our review of the literature shows that current evidence is lacking on the existence of MCAS or hEDS as separate or significant clinical entities. Studies proposing a relationship between the three clinical entities are either biased or based on outdated criteria. The reason behind the purported association of these entities stems from an overlapping pool of vague, subjective symptoms, which is inadequate evidence to conclude that any such relationship exists.

Understanding experiences, perceptions, and perspectives of patients with a mast cell disorder (MCD), including cutaneous mastocytosis, systemic mastocytosis, mast cell activation syndromes, and hereditary α-tryptasemia, is an important aspect of successful care, treatment, and informed development of novel therapies. This article reviews existing studies and presents new data on MCD patient perceptions regarding medical care, symptoms, allergies/sensitivities, triggers, future health/disease progression, treatment, impact on daily living, quality of life, support needs, and concerns regarding possible familial disease. Discussion includes aspects affecting the MCD community that require further consideration and development.

BACKGROUND: Rituximab (Rituxan) hypersensitivity (RITS) can be severe and limits the ability to further administer the treatment. Understanding its pattern and desensitization may permit administration in difficult cases.
OBJECTIVE: Analyze RITS patient characteristics, hypersensitivity pattern, and desensitization outcomes to optimize management.
METHODS: Twenty-five patients with RITS were referred to the Allergy/Immunology Unit at Massachusetts General Hospital over 5 1/2 years. Their clinical reaction patterns were analyzed. Drug desensitizations were performed using 3 related continuous intravenous protocols that were chosen on the basis of clinical history, skin test reactivity, and the patient\'s previous desensitization outcomes.
RESULTS: Of the 25 referred patients, 23 had lymphoma of various types. The 25 patients underwent 170 continuous intravenous desensitizations based on 3 related protocols, with most based on the intermediate protocol. All but 2 desensitizations were completed successfully. Overall 24% of the desensitizations were complicated by hypersensitivity reactions. Two patients with serum sickness and a patient with mast cell disorder were also successfully managed. The average hypersensitivity reaction grade was 3.0 (2-4) before desensitization and 0.41 with desensitization. Skin tests were performed in 18 patients, with 5 patients positive initially and 2 more converted from negative to positive. Skin test status was not helpful for risk stratification for hypersensitivity reactions. Tryptase level was elevated during 21% of desensitizations with reactions but rare among asymptomatic desensitizations.
CONCLUSIONS: Nearly all patients with severe sensitivity to rituximab can be successfully desensitized. IgE-mediated mechanism and mast cell degranulation, in addition to cytokine release syndrome and tumor lysis syndrome, may contribute to a significant portion of hypersensitivity reactions among patients with RITS.

OBJECTIVE: Systemic mastocytosis (SM) is a disorder characterized by the excessive accumulation of clonally derived mast cells in various tissues. When triggered, mast cells release large amounts of histamine, prostaglandins and leukotrienes. Leukotriene E4 (LTE4) is the primary stable metabolite of total cysteinyl leukotrienes. We hypothesized that secretion of LTE4 would be increased in SM and could be used alone or in combination with current urinary biomarkers to optimize screening for SM.
METHODS: LTE4 was measured by liquid chromatography followed by tandem mass spectrometry (LC-MS/MS). Analytical assay validation was performed using residual urine specimens. LTE4 results were normalized to urine creatinine for clinical use. Reference interval was established using a healthy volunteer cohort. Clinical sensitivity and specificity for SM detection were determined by measuring urinary biomarkers (LTE4, N-methyl histamine [NMH] and 11β-prostaglandin F2α [BPG]) in a cohort of 409 patients referred to allergy specialists, 66 (16%) of which were diagnosed with SM.
RESULTS: Urinary LTE4 measurement was accurate, precise and linear across a range of 31-3020pg/mL. The 95th percentile of the reference interval population was <104pg/mg creatinine. Median urine LTE4 concentrations were significantly higher among patients with SM (97pg/mg cr. vs. 50pg/mg cr.; p<0.01). Elevated urinary LTE4 was 48% sensitive and 84% specific for SM. Clinical sensitivity was 53% for BPG (>1000ng/mL) and 71% for NMH (>200ng/mL). Incorporating all three urinary metabolites improved the SM diagnostic sensitivity to 97%, with minimal change in specificity.
CONCLUSIONS: We have developed a sensitive and precise LC-MS/MS assay for quantitation of LTE4 in urine. Incorporating LTE4 into a panel including BPG and NMH provides a much-needed screening tool for a complicated disease with non-specific symptoms and invasive confirmatory testing.

BACKGROUND: Mast cell diseases include mastocytosis and mast cell activation syndromes, some of which have been shown to involve clonal defects in mast cells that result in abnormal cellular proliferation or activation. Numerous clinical studies of mastocytosis have been published, but no population-based comprehensive surveys of patients in the United States have been identified. Few mast cell disease specialty centers exist in the United States, and awareness of these mast cell disorders is limited among nonspecialists. Accordingly, information concerning the experiences of the overall estimated population of these patients has been lacking.
OBJECTIVE: To identify the experiences and perceptions of patients with mastocytosis, mast cell activation syndromes, and related disorders, The Mastocytosis Society (TMS), a US based patient advocacy, research, and education organization, conducted a survey of its members and other people known or suspected to be part of this patient population.
METHODS: A Web-based survey was publicized through clinics that treat these patients and through TMS\'s newsletter, Web site, and online blogs. Both online and paper copies of the questionnaire were provided, together with required statements of consent.
RESULTS: The first results are presented for 420 patients. These results include demographics, diagnoses, symptoms, allergies, provoking factors of mast cell symptoms, and disease impact.
CONCLUSIONS: Patients with mastocytosis and mast cell activation syndromes have provided clinical specialists, collaborators, and other patients with information to enable them to explore and deepen their understanding of the experiences and perceptions of people coping with these disorders.