Odynophagia in a young adult: revisiting herpetic esophagitis and eosinophilic esophagitis.

An immunocompetent man in his 20s presented with a 24-hour history of severe odynophagia, nausea, vomiting and throat pain. Esophagogastroduodenoscopy (EGD) revealed severe esophagitis with ulcerated mucosa, exudative debris, haemorrhage and multiple erosions. Biopsy of the oesophageal tissue demonstrated marginated chromatin, multinucleated giant cells and molding of nuclei, consistent with herpes simplex virus esophagitis (HSE). Treatment with oral acyclovir led to the complete resolution of symptoms. The patient subsequently developed dysphagia again, 8 months later. EGD showed furrowing and concentric rings typical of eosinophilic esophagitis (EoE), a diagnosis confirmed by biopsy. Treatment with a proton pump inhibitor and swallowed topical corticosteroids led to symptomatic improvement. Thus, HSE can occur in immunocompetent hosts and on occasion, HSE may be a harbinger of EoE, as evidenced by our extensive literature review. Mechanical disruption of the mucosal barrier by viruses, facilitating food allergen penetration, and associated immunological signaling abnormalities may be responsible phenomena requiring further elucidation.

Dupilumab-induced ocular surface disease: a primer.

The management of atopic diseases has been revolutionised by precision therapies and biological drugs that target specific immune proteins. This report elucidates a unique complication from the use of the monoclonal antibody, dupilumab, that primary care providers and subspecialists need to be aware of. A patient in her 40s consulted us for severe atopic asthma, food allergy and eczema involving the face and body. She had previously failed treatments and was started on dupilumab (which binds to the interleukin-4 [IL4] receptor and inhibits both IL-4 and IL-13). She quickly achieved remission of asthma, rhinitis and eczema. Therapy was, however, complicated by severe blepharoconjunctivitis, dry eyes and periorbital dermatitis, consistent with dupilumab-induced ocular surface disease and dupilumab-associated mucin deficiency. Following aggressive treatment of ocular disease, the patient was able to continue dupilumab injections for asthma and eczema. It is presumed that dupilumab-induced cytokine imbalance results in ocular goblet cell dysfunction, mucin deficiency and ocular disease.

Mastocytosis and Mast Cell Activation Disorders: Clearing the Air.

Mast cells are derived from hematopoietic stem cell precursors and are essential to the genesis and manifestations of the allergic response. Activation of these cells by allergens leads to degranulation and elaboration of inflammatory mediators, responsible for regulating the acute dramatic inflammatory response seen. Mast cells have also been incriminated in such diverse disorders as malignancy, arthritis, coronary artery disease, and osteoporosis. There has been a recent explosion in our understanding of the mast cell and the associated clinical conditions that affect this cell type. Some mast cell disorders are associated with specific genetic mutations (such as the D816V gain-of-function mutation) with resultant clonal disease. Such disorders include cutaneous mastocytosis, systemic mastocytosis (SM), its variants (indolent/ISM, smoldering/SSM, aggressive systemic mastocytosis/ASM) and clonal (or monoclonal) mast cell activation disorders or syndromes (CMCAS/MMAS). Besides clonal mast cell activations disorders/CMCAS (also referred to as monoclonal mast cell activation syndromes/MMAS), mast cell activation can also occur secondary to allergic, inflammatory, or paraneoplastic disease. Some disorders are idiopathic as their molecular pathogenesis and evolution are unclear. A genetic disorder, referred to as hereditary alpha-tryptasemia (HαT) has also been described recently. This condition has been shown to be associated with increased severity of allergic and anaphylactic reactions and may interact variably with primary and secondary mast cell disease, resulting in complex combined disorders. The role of this review is to clarify the classification of mast cell disorders, point to molecular aspects of mast cell signaling, elucidate underlying genetic defects, and provide approaches to targeted therapies that may benefit such patients.

Mechanisms Governing Anaphylaxis: Inflammatory Cells, Mediators, Endothelial Gap Junctions and Beyond.

Anaphylaxis is a severe, acute, life-threatening multisystem allergic reaction resulting from the release of a plethora of mediators from mast cells culminating in serious respiratory, cardiovascular and mucocutaneous manifestations that can be fatal. Medications, foods, latex, exercise, hormones (progesterone), and clonal mast cell disorders may be responsible. More recently, novel syndromes such as delayed reactions to red meat and hereditary alpha tryptasemia have been described. Anaphylaxis manifests as sudden onset urticaria, pruritus, flushing, erythema, angioedema (lips, tongue, airways, periphery), myocardial dysfunction (hypovolemia, distributive or mixed shock and arrhythmias), rhinitis, wheezing and stridor. Vomiting, diarrhea, scrotal edema, uterine cramps, vaginal bleeding, urinary incontinence, dizziness, seizures, confusion, and syncope may occur. The traditional (or classical) pathway is mediated via T cells, Th2 cytokines (such as IL-4 and 5), B cell production of IgE and subsequent crosslinking of the high affinity IgE receptor (FcεRI) on mast cells and basophils by IgE-antigen complexes, culminating in mast cell and basophil degranulation. Degranulation results in the release of preformed mediators (histamine, heparin, tryptase, chymase, carboxypeptidase, cathepsin G and tumor necrosis factor alpha (TNF-α), and of de novo synthesized ones such as lipid mediators (cysteinyl leukotrienes), platelet activating factor (PAF), cytokines and growth factors such as vascular endothelial growth factor (VEGF). Of these, histamine, tryptase, cathepsin G, TNF-α, LTC4, PAF and VEGF can increase vascular permeability. Recent data suggest that mast cell-derived histamine and PAF can activate nitric oxide production from endothelium and set into motion a signaling cascade that leads to dilatation of blood vessels and dysfunction of the endothelial barrier. The latter, characterized by the opening of adherens junctions, leads to increased capillary permeability and fluid extravasation. These changes contribute to airway edema, hypovolemia, and distributive shock, with potentially fatal consequences. In this review, besides mechanisms (endotypes) underlying IgE-mediated anaphylaxis, we also provide a brief overview of IgG-, complement-, contact system-, cytokine- and mast cell-mediated reactions that can result in phenotypes resembling IgE-mediated anaphylaxis. Such classifications can lead the way to precision medicine approaches to the management of this complex disease.

Subcutaneous Immunoglobulin Therapy with IgPro20 in Patients with Stiff Person Syndrome and Primary Immunodeficiency Disease.

Stiff Person Syndrome (SPS), a rare autoimmune neurologic disorder characterized by fluctuating muscle spasms and rigidity, is mediated by autoantibodies to glutamic acid decarboxylase (GAD) antibodies. Symptoms of SPS have been shown to improve after administration of intravenous immunoglobulin (IVIG) however, there is a paucity of information regarding use of SCIg in SPS. Four patients with Stiff Person Syndrome were treated with SCIgPro20 for a period between 31 to 101 months. Most reactions were local and mild. All patients reported improvement in spasticity, and 2 patients reported improvement in seizure frequency. SCIgPro20 was well tolerated in patients with SPS and was associated with improvement in symptoms.

Critical Care Management of the Patient With Anaphylaxis: A Concise Definitive Review.

OBJECTIVES: Anaphylaxis is a rapidly progressive life-threatening syndrome manifesting as pruritus, urticaria, angioedema, bronchospasm and shock. The goal of this synthetic review is to provide a practical, updated approach to the evaluation and management of this disorder and associated complications. DATA SOURCES: A MEDLINE search was conducted with the MeSH of anaphylaxis, anaphylactic reaction, anaphylactic shock, refractory anaphylaxis and subheadings of diagnosis, classification, epidemiology, complications and pharmacology. The level of evidence supporting an intervention was evaluated based on the availability of randomized studies, expert opinion, case studies, reviews, practice parameters and other databases (including Cochrane). STUDY SELECTION: Selected publications describing anaphylaxis, clinical trials, diagnosis, mechanisms, risk factors and management were retrieved (reviews, guidelines, clinical trials, case series) and their bibliographies were also reviewed to identify relevant publications. DATA EXTRACTION: Data from the relevant publications were reviewed, summarized and the information synthesized. DATA SYNTHESIS: This is a synthetic review and the data obtained from a literature review was utilized to describe current trends in the diagnosis and management of the patient with anaphylaxis with a special emphasis on newer evolving concepts of anaphylaxis endotypes and phenotypes, management of refractory anaphylaxis in the ICU setting and review of therapeutic options for the elderly patient, or the complicated patient with severe cardiorespiratory complications. Most of the recommendations come from practice parameters, case studies or expert opinions, with a dearth of randomized trials to support specific interventions. CONCLUSION: Anaphylaxis is a rapidly progressive life-threatening disorder. The critical care physician needs to be familiar with the diagnosis, differential diagnosis, evaluation, and management of anaphylaxis. Skilled intervention in ICUs may be required for the patient with complicated, severe, or refractory anaphylaxis.

The enigmatic immunoglobulin G4-related disease and its varied cardiovascular manifestations.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disease characterised by multiorgan lymphoplasmacytic infiltration, obliterative phlebitis and storiform fibrosis. It can be associated with cardiovascular pathology. The objective of this narrative review is to summarise the published literature on cardiovascular manifestations of IgG4-RD and to provide a basis for diagnosis and management of the condition by the practising cardiologist.We propose the following categorisations of cardiovascular IgG4-RD: aortitis, medium-vessel arteritis, pulmonary vascular disease, phlebitis, valvulopathy, pericarditis, myocardial disease and antineutrophilic cytoplasmic antibody-associated vasculitis. We also review herein developments in radiological diagnosis and reported medical and surgical therapies. Cardiovascular lesions frequently require procedural and/or surgical interventions, such as aortic aneurysm repair and valve replacement. IgG4-RD of the cardiovascular system results in serious complications that can be missed if not evaluated aggressively. These are likely underdiagnosed, as clinical presentations frequently mimic cardiovascular disease due to more common aetiologies (myocardial infarction, abdominal aortic aneurysm and so on). While systemic corticosteroids are the mainstay of IgG4-RD treatment, biological and disease-modifying agents are becoming more widely used. Cardiologists should be aware of cardiovascular IgG4-RD as a differential diagnosis, and understand the roles of corticosteroids, disease-modifying agents and biologicals, as well as their integration with surgical approaches. There are several knowledge gaps, including diagnosis, risk factors, pathogenesis and appropriate management in Ig4-RD of the cardiovascular system. Areas lacking well-conducted randomized trials include safety of steroids in the setting of vascular aneurysms and the role of disease-modifying drugs and biological agents in patients with established cardiovascular complications of this multifaceted enigmatic disease.

Common Variable Immune Deficiency and Associated Complications.

Common variable immunodeficiency disorders refer to a relatively common primary immune deficiency group of diseases that present with infectious and inflammatory complications secondary to defects in antibody production and sometimes in cellular immunity. The disorder often presents in middle age or later with recurrent sinopulmonary infections, bronchiectasis, or a plethora of noninfectious complications such as autoimmune disorders, granulomatous interstitial lung disease, GI diseases, malignancies (including lymphoma), and multisystem granulomatous disease resembling sarcoidosis. Infusion of immunoglobulin by IV or subcutaneous is the mainstay of therapy. Management of complications is often difficult as immune suppression may be necessary in these conditions and entails the use of medications and biologicals which may further increase the risk for infections. Specifically, bronchiectasis, granulomatous lymphocytic interstitial lung disease, repeated sinopulmonary infections, and malignancies are sequelae of antibody deficiency that may present to the pulmonologist. This review will provide an updated understanding of the molecular aspects, differential diagnosis, presentations, and the management of common variable immunodeficiency disorders.

Anaphylaxis.

Anaphylaxis is a systemic, life-threatening disorder triggered by mediators released by mast cells and basophils activated via allergic (IgE-mediated) or nonallergic (non-IgE-mediated) mechanisms. It is a rapidly evolving, multisystem process involving the integumentary, pulmonary, gastrointestinal, and cardiovascular systems. Anaphylaxis and angioedema are serious disorders that can lead to fatal airway obstruction and culminate in cardiorespiratory arrest, resulting in hypoxemia and/or shock. Often, these disorders can be appropriately managed in an outpatient setting; however, these conditions can be severe enough to warrant evaluation of the patient in the ED and in some cases, hospitalization, and management in an ICU. Reports suggest that underdiagnosis and undertreatment of anaphylaxis are common. Several new syndromes have been described recently including bird-egg, pork-cat, delayed allergy to mammalian meat and a diverse group of mast cell activation disorders. Conditions such as postural orthostatic tachycardia syndrome, carcinoid syndrome, Munchausen stridor, and factitious anaphylaxis can present similarly and need to be included in the differential diagnosis. Anaphylaxis is a clinical diagnosis, but plasma tryptase and urinary histamine levels are often elevated, allowing diagnostic confirmation; however, diagnostic testing should not delay treatment as results may not be immediately available. The sine qua non of treatment is avoidance of any known triggers and epinephrine, which should never be delayed if this disorder is suspected. Secondary treatments include fluids, bronchodilators, antihistamines, and glucocorticoids. Patients with cardiopulmonary arrest or airway or vascular compromise require mechanical ventilation, vasopressors, and other advanced life support in the ICU.

Nafcillin-Induced Allergic Eosinophilic Cholestatic Hepatitis.

A 71-year-old female with no history of liver disease or antibiotic allergy developed jaundice with elevated liver enzymes and eosinophilia following treatment with nafcillin for septic arthritis. Further workup demonstrated hepatocellular dysfunction and liver biopsy showed expansion of portal tracts by lymphocytes and eosinophils consistent with a hypersensitivity reaction. Nafcillin and related antibiotics were withdrawn, and her symptoms resolved 3 months later. We searched PubMed using terms of "nafcillin cholestasis" and "nafcillin hepatitis", and a review of the literature showed other reports of nafcillin-induced hepatitis and cholestasis. Avoidance and on occasion the guarded use of glucocorticoids can lead to recovery from the insult. This case report shows that while rare, nafcillin can cause cholestatic hepatitis through a likely eosinophil-mediated hypersensitivity reaction. Further studies are needed to elucidate the mechanism of this reaction.