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Edited by Jeremy Mills, MSN, PMHNP-BCPeninsula, a Division of Parkwest Medical Center, Knoxville,TN, USAOn a sunny summer afternoon many years ago, when I was a newly hatched nurse, I walked into a...

Macrophagic activation syndrome (SAM) or Hemophagocytic lymphohistiocytosis is a clinical-biological entity of non-specific proliferation and activation of macrophages of the reticulohistiocytic system, with phagocytosis of the figurative elements of blood. It is a rare pathology combining non-specific clinical and biological signs and images of hemophagocytosis. It can be primary or acquired secondary to an infection, an autoimmune or neoplastic disease. While T or NK lymphomas are the classic causes of reactive SAM and its association with Hodgkin lymphoma is exceptional. This is a diagnostic and therapeutic emergency given the risk of development towards a fatal multivisceral failure due to an absence of appropriate support. This is a report of a case of SAM revealing a case of Hodgkin lymphoma in a 35-year-old patient.

Los niños son más propensos a los efectos adversos de los inhibidores selectivos de la recaptación de serotonina que los adultos. El objetivo del presente trabajo es revisar la bibliografía sobre la manía y la hipomanía inducida por estos antidepresivos. Gran parte de los jóvenes con diagnóstico de trastorno bipolar habían estado expuestos a este tipo de fármacos. La hipomanía asociada a antidepresivos en niños con trastornos de ansiedad es tan relevante como la de aquellos que previamente habían recibido un diagnóstico de depresión. Como limitación, en los trabajos seleccionados, el síndrome de activación podía incluir o no a la (hipo)manía. Al indicar un antidepresivo debemos ser sumamente prudentes y hacer especial énfasis en el análisis riesgo-beneficio. Es imprescindible realizar una búsqueda exhaustiva de antecedentes familiares de trastorno bipolar junto con una pesquisa de antecedentes personales y un minucioso análisis de la semiología de nuestros pacientes debido a los riesgos de (hipo)manía.

The American Initiative in Mast Cell Diseases (AIM) held its inaugural investigator conference at Stanford University School of Medicine in May 2019. The overarching goal of this meeting was to establish a Pan-American organization of physicians and scientists with multidisciplinary expertise in mast cell disease. To serve this unmet need, AIM envisions a network where basic, translational, and clinical researchers could establish collaborations with both academia and biopharma to support the development of new diagnostic methods, enhanced understanding of the biology of mast cells in human health and disease, and the testing of novel therapies. In these AIM proceedings, we highlight selected topics relevant to mast cell biology and provide updates regarding the recently described hereditary alpha-tryptasemia. In addition, we discuss the evaluation and treatment of mast cell activation (syndromes), allergy and anaphylaxis in mast cell disorders, and the clinical and biologic heterogeneity of the more indolent forms of mastocytosis. Because mast cell disorders are relatively rare, AIM hopes to achieve a coordination of scientific efforts not only in the Americas but also in Europe by collaborating with the well-established European Competence Network on Mastocytosis.

Graphical abstract Schematic diagram of the complications, possible treatments, and potential resistant target genes of IVIG resistant KD patient., Kawasaki disease is an acute childhood self-limited vasculitis, causing the swelling or inflammation of medium-sized arteries, eventually leading to cardiovascular problems such as coronary artery aneurysms. Acetylsalicylic acid combined with intravenous immunoglobulin (IVIG) is the standard treatment of Kawasaki disease (KD). However, a rising number of IVIG resistant cases were reported with severe disease complications such as the KD Shock Syndrome or KD-Macrophage activation syndrome. Recent reports have depicted the overlapped number of children with SARS-CoV-2 and KD, which was called multisystem inflammatory syndrome. Simultaneously, the incidence rate of KD-like diseases are increased after the outbreak of COVID-19, suggesting the virus may be associated with KD. New intervention is important to overcome the problem of IVIG treatment resistance. This review aims to introduce the current pharmacological intervention and possible resistance genes for the discovery of new drug for IVIG resistant KD.

Generalized anxiety disorder (GAD) sometimes exists in the background of social withdrawal and school refusal. Although clinical evidence suggests that selective serotonin reuptake inhibitors (SSRIs) are an effective treatment for GAD, they are not officially approved for GAD in Japan. In addition, it has been established that the use of SSRIs increases the risk for suicide and activation syndrome among young individuals. As such, there is currently little domestic clinical experience in prescribing SSRIs to young patients with GAD. The authors report two cases involving 10-year-old patients with GAD who were treated successfully with escitalopram and experienced subsequent improvement in social withdrawal and school refusal. One patient had autistic spectrum disorder and exhibited self-harm associated with anxiety symptoms, requiring careful use of SSRIs under hospitalization. The other patient was treated at an outpatient clinic without any side effects. In each case, improvement of anxiety symptoms with the use of SSRIs facilitated the introduction of psychoeducation and psychotherapy. It is important to accurately diagnose GAD, which may exist in the background of patients exhibiting social withdrawal and school refusal, and to treat the disorder appropriately. J. Med. Invest. 67 : 355-357, August, 2020.

Our current recommendations for diagnosing and treating primary mast cell (MC) activation syndrome make use of the latest studies and consensus guidelines for clinically recognizing systemic anaphylaxis in real time, regardless of whether allergen-triggered or other pathways are involved; our current understanding of the biomarkers secreted by activated MCs that best discriminate this disorder from other conditions; and the therapeutic drugs that might selectively affect those mediators or MCs themselves. Finding familial or somatic mutations of genes that cause MCs to be hyperactivatable would extend our diagnostic tools and potentially indicate new therapeutic interventions, targeting either the mutated gene product or the associated molecular pathway. In conclusion, we trust that the clinical, laboratory, and therapeutic criteria for primary MC activation syndromes described herein will provide clinicians with practical criteria of sufficient sensitivity and specificity to diagnose most cases without overdiagnosing the disorder in patients who likely have other conditions.

Background: Mast cells (MCs) have been implicated in a spectrum of allergic, immunologic, and infectious inflammatory conditions that involve different organ systems. MC activation can occur through several different surface receptors other than the well known IgE mediated pathway. Methods: We use two representative case reports from our practice to summarize what is currently known about MCAS disorders (reality) so that the clinician can more easily differentiate these conditions from other complex unexplained conditions that are being associated with MC activation (myth). Results: Many complex MC-related conditions, such as clonal MC diseases, have been well characterized but other MC-related disorders, such as MC activation syndrome (MCAS) and idiopathic anaphylaxis, still remain poorly defined. The current consensus recommendations for a diagnosis of MCAS require clinical symptoms of anaphylaxis that correlate with elevation of a MC activation biomarker(s), which improves with H1-antihistamines. Conclusion: Clinical symptoms of MCAS can overlap with other conditions, including neurogenic disorders, e.g., dysautonomia, which necessitate the importance for the clinician to render an accurate diagnosis so that appropriate treatment is provided.

The American Initiative in Mast Cell Diseases (AIM) held its inaugural investigator conference at Stanford University School of Medicine in May 2019. The overarching goal of this meeting was to establish a Pan-American organization of physicians and scientists with multidisciplinary expertise in mast cell disease. To serve this unmet need, AIM envisions a network where basic, translational, and clinical researchers could establish collaborations with both academia and biopharma to support the development of new diagnostic methods, enhanced understanding of the biology of mast cells in human health and disease, and the testing of novel therapies. In these AIM proceedings, we highlight selected topics relevant to mast cell biology and provide updates regarding the recently described hereditary alpha-tryptasemia. In addition, we discuss the evaluation and treatment of mast cell activation (syndromes), allergy and anaphylaxis in mast cell disorders, and the clinical and biologic heterogeneity of the more indolent forms of mastocytosis. Because mast cell disorders are relatively rare, AIM hopes to achieve a coordination of scientific efforts not only in the Americas but also in Europe by collaborating with the well-established European Competence Network on Mastocytosis., The research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) (award no. R13TR002722 to J.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank The Mast Cell Disease Society, Inc (TMS), a national 501c3 nonprofit, for their partnership and support of AIM, for patient-centered research, and for sponsoring international physicians at this inaugural meeting. J.G. expresses gratitude for the support of the Charles and Ann Johnson Foundation, the staff of the Stanford Mastocytosis Center, and the Stanford Cancer Institute Innovation Fund. M.C., J.J.L., and D.D.M. are supported in part by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH. D.F.D. is supported by the Asthma and Allergic Diseases Cooperative Research Centers Opportunity Fund (award no. U19AI07053 from the NIH). P.V. has been supported by the Austrian Science Fund (FWF) (grant nos. F4701-B20, F4704-B20, and P32470-B).

"Activation syndrome" represents a cluster of symptoms of excessive emotional arousal or behavioral activation, which emerges after the first few weeks of antidepressant treatment or a dose increase and resolves with dose reduction or cessation of treatment. It was reported after treatment with selective serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitor group of agents, but no case of activation syndrome has been reported with the norepinephrine reuptake inhibitor group. Atomoxetine is a norepinephrine reuptake inhibitor and nonstimulant and is used to manage symptoms of attention-deficit/hyperactivity disorder (ADHD). Atomoxetine-related symptoms of mania and hypomania were reported in literature previously. Here, we report a case of activation syndrome arising after atomoxetine (ATX) dose titration in a prepubertal male child with ADHD. Differentiation of activation symptoms from mania/hypomania symptoms after treatment with ATX may be important for the clinicians to manage the adverse effects and understand the risk factors behind activation syndrome with use of ATX in children and adolescents diagnosed with ADHD.

Objectives One-fifth of Covid-19 patients suffer a severe course of Covid-19 infection; however, the specific causes remain unclear. Mast cells (MCs) are activated by SARS-CoV-2. Although only recently recognized, MC activation syndrome (MCAS), usually due to acquired MC clonality, is a chronic multisystem disorder with inflammatory and allergic themes, and an estimated prevalence of 17%. This paper describes a novel conjecture explaining how MCAS might cause a propensity for severe acute Covid-19 infection and chronic post-Covid-19 illnesses. Methods Observations of Covid-19 illness in patients with/without MCAS were compared with extensive clinical experience with MCAS. Results The prevalence of MCAS is similar to that of severe cases within the Covid-19-infected population. Much of Covid-19’s hyperinflammation is concordant with manners of inflammation which MC activation can drive. Drugs with activity against MCs or their mediators have preliminarily been observed to be helpful in Covid-19 patients. None of the authors’ treated MCAS patients with Covid-19 suffered severe infection, let alone mortality. Conclusions Hyperinflammatory cytokine storms in many severely symptomatic Covid-19 patients may be rooted in an atypical response to SARS-CoV-2 by the dysfunctional MCs of MCAS rather than a normal response by normal MCs. If proven, this theory has significant therapeutic and prognostic implications.

The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm.

The United States Food and Drug Administration issued a Black Box warning in October 2004 after placebo-controlled trials of antidepressant medications found an increased risk of suicidal thoughts and behaviors among children and adolescents taking antidepressant medications relative to placebo. Subsequently, some researchers have concluded that the Black Box warning caused severe unintended consequences; specifically, they have argued that the warning led to reduced use of antidepressants among youth, which led to more suicides. In this paper, we critically examine research regarding the Black Box warning’s alleged deleterious consequences. One study claimed that controlled trials did not actually find an increased risk of suicidality among youth taking fluoxetine relative to those taking placebo, but its measure of suicidality is likely invalid. We found that ecological time series studies claiming that decreasing antidepressant prescriptions are linked to higher rates of suicide attempts or actual suicides among youth were methodologically weak. These studies exhibited shortcomings including: selective use of time points, use of only a short-term time series, lack of performing statistical analysis, not examining level of severity/impairment among participants, inability to control confounding variables, and/or use of questionable measures of suicide attempts. Further, while some time-series studies claim that increased antidepressant prescriptions are related to fewer youth suicides, more recent data suggests that increasing antidepressant prescriptions are related to more youth suicide attempts and more completed suicides among American children and adolescents. We also note that case-control studies show increased risk of suicide attempts and suicide among youth taking antidepressants, even after controlling for some relevant confounds. As clinical trials have the greatest ability to control relevant confounds, it is important to remember such trials demonstrated increased risk of suicidality adverse events among youth taking antidepressants. The Black Box warning is firmly rooted in solid data whereas attempts to claim the warning has caused harm are based on quite weak evidence.

Objective To determine the characteristics of the activation syndrome (AS) that predict the emergence or worsening of suicidal ideation (SI) in the first month of antidepressant treatment with tianeptine, as well as the temporal relationship between both conditions. Method A naturalistic sample of 2422 depressed outpatients starting a new antidepressant treatment with tianeptine was assessed at 2, 4 and 6 weeks of follow-up using validated questionnaires. Four main dimensions of AS were examined: impulsivity, sleep problems, anxiety and agitation. Results The emergence of an AS was more likely in long-lasting depressive episodes, but less likely if the patient responded to the antidepressant or benzodiazepines were added as an add-on treatment. Treatment-emergent SI was strongly associated to the presence of an AS, particularly in case of sleep problems (OR = 8.42) or impulsivity upsurges (OR = 3.89), even after adjustment for all relevant confounding factors. Conclusions Our findings suggest a dose-effect mechanism modulating the relationship between treatment-related SI and AS. AS symptoms may need to be monitored closely in the weeks that follow the introduction of an antidepressant treatment.

Macrophagic Activation Syndrome (MAS) is a rare disorder and is thought to result from non-malignant activation and proliferation of macrophages and T-cells. It can be of primary or secondary origin and its prognosis is often poor. Authors report a case of a three-year-old boy admitted in the intensive care unit for MAS secondary to an overdose of sodium valproate to remind practitioners to think about it in the presence of a febrile pancytopenia.

Background Macrophage activation syndrome (MAS) is an uncommon but serious complication of systemic lupus erythematosus (SLE). We aimed to identify factors associated with MAS among adult hospitalized SLE patients. Methods Within the Brigham and Women’s Hospital (BWH) Lupus Center Registry, we identified adult SLE patients > age 17 who had been hospitalized from 1970 to 2016, with either ferritin > 5000 ng/ml during admission or “macrophage activation syndrome” or “MAS” in discharge summary. We confirmed MAS by physician diagnosis in medical record review. We matched each hospitalized SLE patient with MAS to four SLE patients hospitalized without MAS (by SLE diagnosis date ±1 year). We employed conditional logistic regression models to identify clinical factors associated with MAS among hospitalized SLE patients. Results Among 2094 patients with confirmed SLE, we identified 23 who had a hospitalization with MAS and compared them to 92 hospitalized without MAS. Cases and controls had similar age at SLE diagnosis (29.0 vs. 30.5, p = 0.60), and hospital admission (43.0 vs. 38.3, p = 0.80), proportion female (78% vs. 84%, p = 0.55), and time between SLE diagnosis and hospitalization (1971 vs. 1732 days, p = 0.84). Arthritis (OR 0.04 (95% CI 0.004–0.35)) and hydroxychloroquine use (OR 0.18 (95% CI 0.04–0.72)) on admission were associated with decreased MAS risk. Admission Systemic Lupus Erythematosus Disease Activity Index scores (30 vs. 19, p = 0.002) and lengths of stay (16 days vs. 3 days, p Conclusions In this case-control study of hospitalized adult SLE patients, arthritis and hydroxychloroquine use at hospital admission were associated with decreased MAS risk. Further studies are needed to validate these factors associated with lowered MAS risk.

Mast cell (MC) activation syndrome (MCAS) is a collection of illnesses of inappropriate MC activation with little to no neoplastic MC proliferation, distinguishing it from mastocytosis. MCAS presents as chronic, generally inflammatory multisystem polymorbidity likely driven in most by heterogeneous patterns of constitutively activating mutations in MC regulatory elements, posing challenges for identifying optimal mutation-targeted treatment in individual patients. Targeting commonly affected downstream effectors may yield clinical benefit independent of upstream mutational profile. For example, both activated KIT and numerous cytokine receptors activate the Janus kinases (JAKs). Thus, JAK-inhibiting therapies may be useful against the downstream inflammatory effects of MCAS. The oral JAK1/JAK3 inhibitor, tofacitinib, is currently approved for rheumatoid arthritis and is in clinical trials for other chronic inflammatory disorders. Herein, we report two patients with MCAS who rapidly gained substantial symptomatic response to tofacitinib. Their improvement suggests need for further evaluation of this class of drugs in MCAS treatment.

Introduction: The Adult Onset Still’s Disease (ASD) is a systemic auto-inflammatory affection of unknown cause seldom described in sub-Saharan Africa. We report 3 observations of ASD illustrating the diagnostic and therapeutic difficulties of this affection in our areas. Observation 1: Our first patient is a 56 years old schoolteacher presenting an ASD in its chronic articular form. She had been followed for an inflammatory arthralgia for 10 years and of the pharyngal pains without exact diagnosis. She presented ASD’s criteria of Yamaguchi and of Fautrel. The prednisone was begun at the dose of 0.8 mg/kg/day with fast appearance of a progressive muscular weakness. Use of methotrexate at a rate of 15 mg per week, associated with low dose of prednisone was effective in long-term without any flare of the disease so far. Observation 2: Our second patient is a 30 years old dressmaker presenting an ASD in its complicated systemic form of lymphohistiocytic activation syndrome. She validated the criteria of Yamaguchi and Fautrel for ASD. She also presented resistance to corticosteroid therapy. The evolution was marked by a hospital-acquired septicemia and a multi-organ failure leading to death. The diagnosis was retrospectively confirmed after that, with the low level of the glycosylated ferritin serum value. Observation 3: The third patient is a 22 years old Guinean student who presented prolonged fever and inflammatory polyarthralgia without articular deformation. He had been misdiagnosed for ASD with diagnostic wandering of several months. He was treated successfully with prednisone after set up of ASD diagnosis according common criteria. Corticosteroid therapy was stopped after 8 months without any relapse noted so far. Conclusion: Caring for ASD is difficult in our context mainly because of high cost of several explorations needed to set up its exact diagnosis while making differential one. Evolution under corticosteroid therapy is usually favorable but diagnostic delay may lead to severe complications and death.

WOS: 000496714200004, Objective: Activation syndrome (AS), as described by the U.S. Food and Drug Administration (FDA), comprises 10 bipolar associated symptoms which starts after antidepressant therapy. The aim of this study is to investigate whether there is a relationship between lifetime hypomanic symptoms and the development of AS in patients diagnosed with major depressive disorder (MDD). Method: The study was conducted at Hacettepe University Faculty of Medicine Department of Psychiatry. A total of 60 consecutive outpatients diagnosed with MDD were assessed at three time points; before the initiation of antidepressant therapy (baseline), at 2nd week and at 4th week. At the initial interview the patients completed the Hypomania Checklist-32 (HCL-32) in order to assess the lifetime history of hypomanic symptoms. Barnes Akathisia Rating Scale (BARS), Hamilton Rating Scale for Depression (HAM-D), Hamilton Anxiety Rating Scale (HAM-A) and Young Mania Rating Scale (YMRS) were utilized to detect the symptoms of AS at each assessment. Results: AS was detected in 25 (41.7%) patients. The most prevalent symptoms of AS were insomnia (31.7%), anxiety (25%) and irritability (15%). A significant difference was found in the HCL-32 scores of patients with and without AS. A moderate correlation between the number of AS symptoms and HSL-32 test scores were also determined. Conclusion: AS development was more common among the depressed patients with lifetime history of hypomanic symptoms. Given the frequency of misdiagnosis of BPD as MDD, it would be helpful to assess the hypomanic symptoms systematically with scales similar to HSL-32 in depressive patients before prescribing antidepressant medication.

Activation Syndrome (AS) is a side-effect of antidepressants consisting of irritability, mania, self-harm, akathisia, and disinhibition. The current study was conducted to analyze how AS may hinder treatment outcome for multimodal treatment for children and adolescents with Obsessive-Compulsive Disorder.Fifty-six children or adolescents were recruited at two treatment sites in a double-blind randomized-controlled trial where participants received Cognitive-Behavioral Therapy and were randomized to slow titration of sertraline, regular titration of sertraline or placebo.Using a recently developed measure of AS, results suggested that higher average levels of irritability, akathisia, and disinhibition significantly interfered with treatment response and explained 18% of the variance in obsessive-compulsive symptoms during treatment. Interestingly, only session-to-session increases in irritability resulted in a session-to-session increase in obsessive-compulsive symptoms. The observed results were unchanged with the addition of SSRI dosage as a covariate.Results provide empirical support for the proposed hypothesis that AS may hinder multimodal treatment outcome for pediatric OCD. These findings suggest that dosage changes due to AS do not explain why those with higher AS had worse multimodal outcome. Other possible mechanisms explaining this observed disruption are proposed, including how AS may interfere with Cognitive-Behavioral Therapy.

Neurologists and psychiatrists frequently encounter patients whose central and/or peripheral neurologic and/or psychiatric symptoms (NPS) are accompanied by other symptoms for which investigation finds no unifying cause and for which empiric therapy often provides little to no benefit. Systemic mast cell activation disease (MCAD) has rarely been considered in the differential diagnosis in such situations. Traditionally, MCAD has been considered as just one rare (neoplastic) disease, mastocytosis, generally focusing on the mast cell (MC) mediators tryptase and histamine and the suggestive, blatant symptoms of flushing and anaphylaxis. Recently another form of MCAD, MC activation syndrome (MC), has been recognized, featuring inappropriate MC activation with little to no neoplasia and likely much more heterogeneously clonal and far more prevalent than mastocytosis. There also has developed greater appreciation for the truly very large menagerie of MC mediators and their complex patterns of release, engendering complex, nebulous presentations of chronic and acute illness best characterized as multisystem polymorbidity of generally inflammatory ± allergic themes--including very wide arrays of central and peripheral NPS. Significantly helpful treatment--including for neuropsychiatric issues--usually can be identified once MCAD is accurately diagnosed. We describe MCAD's pathogenesis, presentation (focusing on NPS), and therapy, especially vis-à-vis neuropsychotropes. Since MCAD patients often present NPS, neurologists and psychiatrists have the opportunity, in recognizing the diagnostic possibility of MCAD, to short-circuit the often decades-long delay in establishing the correct diagnosis required to identify optimal therapy.

Purpose This article reviews the diagnostically challenging presentation of mast cell activation disease (MCAD) and current thoughts regarding interactions between microbiota and MCs. Methods A search for all studies on interactions between mast cells, mast cell activation disease, and microbiota published on pubmed.gov and scholar.google.com between 1960 and 2015 was conducted using the search terms mast cell, mastocyte, mastocytosis, mast cell activation, mast cell activation disease, mast cell activation syndrome, microbiome, microbiota. A manual review of the references from identified studies was also conducted. Studies were excluded if they were not accessible electronically or by interlibrary loan. Findings Research increasingly is revealing essential involvement of MCs in normal human biology and in human disease. Via many methods, normal MCs—present sparsely in every tissue—sense their environment and reactively exert influences that, directly and indirectly, locally and remotely, improve health. The dysfunctional MCs of the "iceberg" of MCAD, on the other hand, sense abnormally, react abnormally, activate constitutively, and sometimes (in mastocytosis, the "tip" of the MCAD iceberg) even proliferate neoplastically. MCAD causes chronic multisystem illness generally, but not necessarily, of an inflammatory ± allergic theme and with great variability in behavior among patients and within any patient over time. Furthermore, the range of signals to which MCs respond and react include signals from the body's microbiota, and regardless of whether an MCAD patient has clonal mastocytosis or the bulk of the iceberg now known as MC activation syndrome (also suspected to be clonal but without significant MC proliferation), dysfunctional MCs interact as dysfunctionally with those microbiota as they interact with other human tissues, potentially leading to many adverse consequences. Implications Interactions between microbiota and MCs are complex at baseline. The potential for both pathology and benefit may be amplified when compositionally variant microbiota interact with aberrant MCs in various types of MCAD. More research is needed to better understand and leverage these interactions.

Selective serotonin reuptake inhibitors (SSRIs) are an efficacious and effective treatment for pediatric obsessive-compulsive disorder (OCD) but have received scrutiny due to a potential side effect constellation called activation syndrome. While recent research introduced a subjective measure of activation syndrome, objective measures have not been tested. This pilot study, using data from a larger randomized-controlled trial, investigated the potential of actigraphy to provide an objective measure of activation symptoms in 44 youths with OCD beginning an SSRI medication regimen. Data were collected over the first four weeks of a multi-site, parallel, double-blind, randomized, placebo controlled psychopharmacological treatment study and statistical modeling was utilized to test how activation syndrome severity predicts daily and nightly activity levels. Results indicated that youths with higher activation symptoms had lower daytime activity levels when treatment averages were analyzed; in contrast youths who experienced onset of activation symptoms one week were more likely to have higher day-time and night-time activity ratings that week. Results support actigraphy as a potential objective measure of activation symptoms. Subsequent studies are needed to confirm these findings and test clinical applications for use by clinicians to monitor activation syndrome during SSRI treatment. National Institutes of Health (5UO1 MH078594-01); NCT00382291.

Antidepressants are being increasingly prescribed for children and adolescents for the treatment of depression, anxiety, and other mental disorders. The selective serotonin reuptake inhibitors (SSRIs) are the major contributors to this trend. Children are especially prone to psychiatric adverse events of SSRIs relative to adults. Recently, attention has been addressed to a specific constellation of emotional and behavioral symptoms associated with SSRI treatment, termed activation syndrome. However, the prevalence, characteristics, and implications of this syndrome have not been systematically examined in the pediatric population. Furthermore, the relationship between SSRI-induced activation and bipolar disorder or other psychiatric adverse events, particularly suicidality and manic conversion, remains unclear. The aim of this review was to report on the current scientific literature on SSRI-induced activation syndrome in young patients and to suggest future directions for research. This information will help to clarify the underlying mechanism of this phenomenon and its prognostic significance and aid clinicians in identifying patients at risk and developing effective management and preventive measures.

Mast cell (MC) disease has long been thought to be just the rare disease of mastocytosis (in various forms, principally cutaneous and systemic), with aberrant MC mediator release at symptomatic levels due to neoplastic MC proliferation. Recent discoveries now show a new view is in order, with mastocytosis capping a metaphorical iceberg now called “MC activation disease” (MCAD, i.e. disease principally manifesting inappropriate MC activation), with the bulk of the iceberg being the recently recognized “MC activation syndrome” (MCAS), featuring inappropriate MC activation to symptomatic levels with little to no inappropriate MC proliferation. Given increasing appreciation of a great menagerie of mutations in MC regulatory elements in mastocytosis and MCAS, the great heterogeneity of MCAD’s clinical presentation is unsurprising. Most MCAD patients present with decades of chronic multisystem polymorbidity generally of an inflammatory ± allergic theme. Preliminary epidemiologic investigation suggests MCAD, while often misrecognized, may be substantially prevalent, making it increasingly important that practitioners of all stripes learn how to recognize its more common forms such as MCAS. We review the diagnostically challenging presentation of MCAD (with an emphasis on MCAS) and current thoughts regarding its biology, epidemiology, natural history, diagnostic evaluation, and treatment.Key messagesRecent discoveries show a new view of the realm of mast cell disease is in order, with mastocytosis capping a metaphorical iceberg now termed “MC activation disease” (MCAD, i.e. disease principally manifesting inappropriate MC activation) and with the bulk of the iceberg being comprised of the recently recognized “MC activation syndrome” (MCAS), featuring inappropriate MC activation to symptomatic levels with little to no inappropriate MC proliferation.Most MCAD patients present with decades of chronic multisystem polymorbidity generally of an inflammatory ± allergic theme, but diagnostic recognition is challenged by great heterogeneity of clinical presentation which may be due to great underlying mutational heterogeneity in assorted mast cell regulatory elements.Although few biomarkers predictive of helpful therapy are yet available, most MCAD patients are able to eventually identify significantly helpful therapy by persistently and methodically stepping through trials of the many treatments shown helpful across this patient population. Recent discoveries show a new view of the realm of mast cell disease is in order, with mastocytosis capping a metaphorical iceberg now termed “MC activation disease” (MCAD, i.e. disease principally manifesting inappropriate MC activation) and with the bulk of the iceberg being comprised of the recently recognized “MC activation syndrome” (MCAS), featuring inappropriate MC activation to symptomatic levels with little to no inappropriate MC proliferation. Most MCAD patients present with decades of chronic multisystem polymorbidity generally of an inflammatory ± allergic theme, but diagnostic recognition is challenged by great heterogeneity of clinical presentation which may be due to great underlying mutational heterogeneity in assorted mast cell regulatory elements. Although few biomarkers predictive of helpful therapy are yet available, most MCAD patients are able to eventually identify significantly helpful therapy by persistently and methodically stepping through trials of the many treatments shown helpful across this patient population.

Traditionally, mast cell activation disease (MCAD) has been considered as just one rare (neoplastic) disease, mastocytosis, focused on the mast cell (MC) mediators tryptase and histamine and the suggestive, blatant symptoms of flushing and anaphylaxis. Recently another form of MCAD, the MC activation syndrome, has been recognized featuring inappropriate MC activation with little to no neoplasia and likely much more heterogeneously clonal and far more prevalent than mastocytosis. Increasing expertise and appreciation has been established for the truly very large menagerie of MC mediators and their complex patterns of release, engendering complex, nebulous presentations of chronic and acute illness best characterized as multisystem polymorbidity of generally inflammatory ± allergic theme. We describe the pathogenesis of MCAD with a particular focus on clinical cardiovascular symptoms and the therapeutic options for MC mediator-induced cardiovascular symptoms.

Activation syndrome is a severe adverse effect caused by antidepressants. It is more frequently induced by paroxetine than by other selective serotonin reuptake inhibitors. However, there have been no descriptions of demented patients with activation syndrome derived from paroxetine. Herein, we report on three cases of dementia with Lewy bodies who suffered from activation syndrome induced by paroxetine. These symptoms rapidly disappeared following discontinuation of paroxetine. The present cases lead us to speculate that paroxetine is injurious to patients with dementia with Lewy bodies.

BACKGROUND: Activation syndrome is a side effect of antidepressants that is thought to carry a potentially increased risk of suicide. However, the incidence of activation syndrome has not been fully investigated and little has been reported on its predictors. The aim of this study was to survey the incidence of activation syndrome and clarify its predictors in a natural clinical setting. METHODS: Among 2,521 new outpatients visiting between August 2003 and March 2005, we retrospectively surveyed the case records of 729 patients who had not taken any antidepressants during the 1 month before presentation and were prescribed antidepressants for 3 months after the initial visit. Patients were classified as developing activation syndrome if they experienced any symptom of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania during the first 3 months. RESULTS: Of the 729 patients, 31 (4.3%) developed activation syndrome. The incidence was not significantly related to gender, age, class of antidepressant, combined use of benzodiazepine, or DSM-IV-TR diagnosis except for personality disorder. Diagnosis of personality disorder was significantly associated with the induction of activation syndrome (odds ratio=4.20, P=0.002). CONCLUSIONS: This study suggests that diagnosis of personality disorder may be a clinical predictor of activation syndrome. Language: en

Mast cell (MC) activation syndrome (MCAS) is a recently recognized, likely prevalent collection of heterogeneous illnesses of inappropriate MC activation with little to no MC neoplasia likely driven by heterogeneous patterns of constitutively activating mutations in MC regulatory elements including various tyrosine kinases (TKs, dominantly KIT). MCAS typically presents as chronic multisystem polymorbidity of generally inflammatory ± allergic theme. As with indolent systemic mastocytosis (SM), treatment of MCAS focuses more against MC mediators than MC neoplasia, but some cases prove refractory even to the TK inhibitor (TKI) imatinib reported useful both in uncommon SM cases not bearing SM's usual imatinib-resistant KIT-D816V mutation and in some cases of MCAS (which rarely bears KIT-D816V). Most allergy is principally a MC activation phenomenon and sunitinib is a multitargeted TKI shown helpful in controlling a murine model of oral allergy syndrome. We present the first report of use of sunitinib in life-threatening MCAS refractory to multiple agents including imatinib achieving immediate, complete, sustained, non-toxic remission suggesting a new option for treatment of aggressive MC disease.

This article reviews evidence that led the Food and Drug Administration to issue a “black box” warning about the risk of “suicidality” (suicidal thoughts and behavior) in children and adolescents during treatment with antidepressants. Re-analysis of data from randomized clinical trials of antidepressants in the pediatric population revealed a significantly greater overall (all drugs across all indications) risk ratio for drug 1.95 (95% Cl, 1.28–2.98) compared to placebo in this sample of approximately 4,000 subjects. The essential message of the “black box” is to remind prescribers and consumers about the importance of monitoring closely for adverse behavioral changes during the initiation of (or changes in) antidepressant therapy. Possible mechanisms that might account for this phenomenon, particularly the so-called activation syndrome, are discussed. Empirical studies are needed to identify the precursors of suicidality and to predict which individuals are most susceptible to adverse behavioral side effects of antidepressants.

Macrophage activation syndrome is the rheumatic disease-associated member of a group of hyperinflammatory syndromes characterized by uncontrolled cytokine storm. In this review, we highlight recent publications related to the pathoetiology of hyperinflammatory syndromes with an emphasis on how this new knowledge will guide our diagnosis, treatment, and future research efforts to better understand these deadly conditions.The heterogeneity of clinical manifestations seen in patients with hyperinflammatory syndromes continues to grow as novel genetic and immunotherapeutic triggers of cytokine storm have been identified. Recent studies characterize unique cytokine and gene expression profiles from patients with different hyperinflammatory syndromes, whereas novel murine models begin to define networks of immune dysregulation thought to drive excessive inflammation in cytokine storm.Emerging evidence suggests hypercytokinemia is the driving cause of immunopathology and morbidity/mortality in hyperinflammatory syndromes. Therefore, approaches to block cytokine function may be fruitful in treating hyperinflammatory syndromes with less toxicity than current therapies. However, not all hyperinflammatory syndromes result in the same pathogenic cytokine profile, implying that a personalized approach will be required for effective use of anticytokine therapies in the treatment of hyperinflammatory syndromes.

Mast cell (MC) activation syndrome (MCAS) is a recently recognized, heterogeneous disease of chronic multisystem inflammation (CMI) ± allergy. MCAS features aberrant MC reactivity and constitutive MC activation with little accumulation of MCs, distinct from mastocytosis [Afrin, Ann Med 48:190-201]. Whether clonality in MCAS is common is debated. Symptoms (sxs) range from mild to disabling, even life-threatening; prevalence may be as high as 17% [Molderings, PLoS One 8(9):e76241], underscoring the importance of studying MCAS. Notwithstanding case reports, small case series, and reviews to date, we report the first systematic characterization of a large MCAS cohort. Methods: Under IRB-approved (Pro00015852, Pro00015857), Mastocytosis Society-sponsored protocols at one center, charts of 298 MCAS pts accrued retrospectively ("retro," diagnosed Nov 2008 - Sep 2012), plus 115 accrued prospectively (diagnosed Apr 2012 - Oct 2013), were reviewed for demographics, comorbidities (probs), sxs, family histories (FHs), physical exam and lab findings. For purposes of follow-up (f/u), data cut-off was June 30, 2014. Data were abstracted by LBA from available records. All were diagnosed with MCAS per criteria [Molderings, J Hematol Oncol 4:10] which in our experience (>1,000 pts) reflects MCAS behavior better than other proposals [e.g., Valent, Int Arch Allergy Immunol 157:215-25]. Blood samples from prospective pts were examined by flow cytometry for clonal MC disease (co-expressing CD45 and CD117 plus CD25 and/or CD2) and tested (ELISA kits, RayBioTech (Norcross, GA)) for elevated (↑) serum levels of cytokines (monocyte colony stimulating factor (M-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3), and tumor necrosis factor alpha (TNF-α)) potentially driving the mild relative monocytosis often seen in MCAS [Afrin, Blood 122:5240]; samples for cytokine testing were kept chilled from collection through assay, including centrifugation. Results: Most of the 413 pts were female (69%) and Caucasian (75%). Median (med) ages at sx onset and diagnosis (dx) were 9 yrs (range 0-88) and 49 yrs (range 16-92). Med time from sx onset to dx was 30 years (range 1-85). Med number of probs was 11 (range 1-66). Med number of sxs was 20 (range 2-84). Med number of FH issues was 4 (range 0-33). Tables 1, 2, and 3 show pts' common clinical and lab characteristics and relative utility of various MC mediators in dx. Frequencies of clinical findings in our pts likely are underestimates due to retro assessment in 298/413 (72%). As reported before for the retro subset [Blood 122:5240], general laboratory abnormalities in these MCAS pts were common, modest, and persistent. Most of our pts (72%) appeared chronically ill at times but overall healthier than expected from their many complaints, contributing to prior dx of somatism in most. Many pts "learned to live with it," no longer reporting some sxs unless asked. In the prospective pts, flow cytometry failed to find the targeted signature of clonal MC disease. Serum M-CSF, GM-CSF, IL-3, and TNF-α levels were assessed and, despite correct negative and positive control results, were not found ↑ in any pt. As of f/u cut-off, 388 pts (94%) were alive, 1 was lost to f/u and 24 pts (6%) had died of many causes (most commonly (25%) cancer). Data were insufficient to calculate meaningful survival statistics from time of dx. Discussion: Long sx duration in MCAS - and cessation, of futility, in reporting sxs - show comprehensive history in pts with CMI is important. Routine lab abnormalities are seen long before dx but are modest and thus given short shrift by busy practitioners, but this study suggests they should spark thought of MCAS in pts with CMI and no unifying dx. Relative utilities of MC mediators for dx in our pts were similar to a recent report [Zenker, Blood 126:5174] and further suggest serum tryptase - while still a good screen for MC neoplasia - poorly reflects MC activation. Conclusions: MCAS is challenging to recognize, but its prevalence, morbidity, chronicity, and ability of most pts to identify helpful therapy merit attention to dx and treatment. Our data, characterizing MCAS more comprehensively than ever before, may facilitate its clinical recognition. More research is needed to identify etiologies (and linkages with chronic inflammatory diseases), facilitate dx, and guide therapy. Disclosures No relevant conflicts of interest to declare.