Disease correlates and clinical relevance of hereditary α-tryptasemia in patients with systemic mastocytosis.

BACKGROUND: Systemic mastocytosis (SM) encompasses a heterogeneous group of clonal disorders characterized by abnormal expansion of mast cells (MCs). Beyond KIT and other genes recurrently mutated in myeloid neoplasms, several genetic variants have been described as predisposing to the development of the disease and influencing its clinical phenotype. Increased copy number variants of the TPSAB1 gene were identified as a cause of nonclonal elevated tryptasemia and defined as hereditary α-tryptasemia (HαT). Moreover, HαT is enriched in patients with SM, where it can affect the incidence of mediator-related symptoms. OBJECTIVE: In a multicenter data set of 444 patients with MC disorders, we aimed to investigate the clinical correlates of germline TPSAB1 copy number gains. METHODS: Droplet digital PCR was performed in all cases to ascertain the presence of HαT. Clinical history along with blood values and bone marrow examination were analyzed. RESULTS: We confirmed a higher incidence of HαT+ cases (n = 59, 13.3%) in patients diagnosed with mastocytosis with respect to the general population (approximately 5%). HαT+ patients were characterized by a lower MC-associated disease burden and higher levels of tryptase. Several disease variables were coherent with this pattern, from bone marrow MC infiltration to MC-related histopathologic traits, which also accounted for a significantly higher incidence of clonal MC activation syndrome in HαT+ (10.2%) compared to HαT- (3.4%, P = .029) patients. We also confirmed that HαT+ carriers had a significantly higher frequency of anaphylaxis, without relevant differences for other clinical manifestations. CONCLUSION: These findings on a large patient series support and extend previous data, and suggest that knowledge of HαT status may be useful for personalized management of patients with SM.

Anti-severe acute respiratory syndrome coronavirus-2 adenoviral-vector vaccines trigger subclinical antiplatelet autoimmunity and increase of soluble platelet activation markers.

To slow down the coronavirus disease 2019 (COVID-19) pandemic an unequalled vaccination campaign was initiated. Despite proven efficacy and safety, a rare but potentially fatal complication of adenoviral-vector vaccines, called vaccine-induced immune thrombotic thrombocytopenia (VITT), has emerged the pathogenesis of which seems to be related to the development of platelet-activating anti-platelet factor 4 (PF4) antibodies. While a few studies have evaluated the incidence of anti-PF4 positivity in anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine recipients, to date no studies have assessed whether an antiplatelet immunological response develops and if this associates with platelet and blood clotting activation. We carried out a prospective study in healthy subjects who received the first dose of ChAdOx1 or Ad26.COV2.S or BNT162b2 vaccines to evaluate platelet-specific and non-specific immune response and in vivo platelet activation and blood clotting activation. Individuals receiving ChAdOx1 and, less so, Ad26.COV2.S developed with high frequency auto- or alloantiplatelet antibodies, increased circulating platelet-derived microvesicles and soluble P-selectin associated with mild blood clotting activation. Our study shows that an immunological reaction involving platelets is not uncommon in individuals receiving anti-SARS-CoV-2 vaccination, especially after ChAdOx1 and Ad26.COV2.S, and that it associates with in vivo platelet and blood clotting activation.

Effectiveness of low-dose intravenous immunoglobulin therapy in minor primary antibody deficiencies: A 2-year real-life experience.

Primary antibody deficiencies (PAD) are the most prevalent group of primary immunodeficiencies (PID) in adults and immunoglobulin replacement therapy (IRT) is the mainstay therapy to improve clinical outcomes. IRT is, however, expensive and, in minor PAD, clear recommendations concerning IRT are lacking. We conducted a retrospective real-life study to assess the effectiveness of low-dose IRT in minor PAD on 143 patients fulfilling European Society for Immunodeficiencies (ESID) diagnostic criteria for immunoglobulin (Ig)G subclass deficiency (IgGSD) or unclassified antibody deficiency (UAD). All patients were treated with intravenous low-dose IRT (0.14 ± 0.06 g/kg/month). Immunoglobulin (Ig) classes and IgG subclasses were measured at baseline and after 1 year of IRT. The annual rate of total infections, upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI) and hospitalizations was measured at baseline and after 1 and 2 years of IRT. After 1 year of IRT significant improvement was demonstrated in: (a) serum IgG (787.9 ± 229.3 versus 929.1 ± 206.7 mg/dl; p < 0.0001); (b) serum IgG subclasses (IgG1 = 351.4 ± 109.9 versus 464.3 ± 124.1, p < 0.0001; IgG2 = 259.1 ± 140 versus 330.6 ± 124.9, p < 0.0001; IgG3 = 50.2 ± 26.7 versus 55.6 ± 28.9 mg/dl, p < 0.002); (c) annual rate of total infections (5.75 ± 3.87 versus 2.13 ± 1.74, p < 0.0001), URTI (1.48 ± 3.15 versus 0.69 ± 1.27; p < 0.005), LRTI (3.89 ± 3.52 versus 1.29 ± 1.37; p < 0.0001) and hospitalizations (0.37 ± 0.77 versus 0.15 ± 0.5; p < 0.0002). The improvement persisted after 2 years of IRT. No significant improvement in URTI annual rate was noted in UAD and in patients with bronchiectasis. In conclusion, low-dose IRT can improve clinical outcomes in UAD and IgGSD patients, providing a potential economical advantage over the standard IRT dose.

Clinical presentation and management practice of systemic mastocytosis. A survey on 460 Italian patients.

Systemic mastocytosis is a rare heterogeneous myeloproliferative neoplasm characterized by abnormal proliferation and activation of mast cells. We describe a large multicentre series of 460 adult patients with systemic mastocytosis, with a diagnosis based on WHO 2008 criteria, in a "real-life" setting of ten Italian centers with dedicated multidisciplinary programs. We included indolent forms with (n = 255) and without (n = 165) skin lesions, smouldering (n = 20), aggressive (n = 28), associated with other hematological diseases mastocytosis (n = 21) and mast cell leukemia (n = 1). This series was uniquely characterized by a substantial proportion of patients with low burden of neoplastic mast cells; notably, 38% of cases were diagnosed using only minor diagnostic criteria according to WHO 2008 classification, underlying the feasibility of early diagnosis where all diagnostic approaches are made available. This has particular clinical relevance for prevention of anaphylaxis manifestations, that were typically associated with indolent forms. In multivariate analysis, the most important features associated with shortened overall survival were disease subtype and age at diagnosis >60 years. Disease progression was correlated with mastocytosis subtype and thrombocytopenia. As many as 32% of patients with aggressive mastocytosis suffered from early evolution into acute leukemia. Overall, this study provides novel information about diagnostic approaches and current presentation of patients with SM and underlines the importance of networks and specialized centers to facilitate early diagnosis and prevent disease-associated manifestations. Am. J. Hematol. 91:692-699, 2016. © 2016 Wiley Periodicals, Inc.

Can selective serotonin reuptake inhibitors/serotonin and norepinephrine reuptake inhibitor antidepressants decrease the "cytokine storm" in the course of COVID-19 pneumonia?

BACKGROUND: Lots of research has been conducted to fight COVID-19 since the outbreak of the pandemic in 2020. The role of "cytokine storm" in the pathogenesis of COVID-19 pneumonia is well known. Relationship between interleukins and depression is still subject matter of the research, but a correlation between interleukin-6 and depressive disorders is proven by now. The aim of this study is to verify differences among interleukin-6 blood levels of inpatients treated with selective serotonin reuptake inhibitors and/or serotonin and norepinephrine reuptake inhibitor before and during hospitalization and of inpatients not treated with these drugs. METHODS: This is an observational study performed during the first wave of SARS Cov-2 pandemic in Italy for three months. The hospitalized patients of Internal Medicine wards and Infectious and Tropical Diseases ward of Azienda Ospedaliero-Universitaria Careggi of Florence for COVID-19 pneumonia have been divided into two subgroups (treated / not treated with antidepressants). Patients admitted to Intensive Care Unit previously have been excluded. Each patient has been evaluated concerning demographic, clinical and therapeutic features. The first dosage of interleukin-6 detected during hospitalization has been noticed. RESULTS: The entire sample included 402 patients and 8.5% (N.=34) had been treated with an antidepressant of the two considered categories before admission until discharge from hospital. Significant lower levels of interleukin-6 of recovered patients of the treated subgroup have been highlighted as compared to recovered patients of not-treated subgroup (12.1 vs. 25.4 P<0.001). These results have been pointed out in spite of higher mean age and more serious comorbidities of the treated subgroup. Nevertheless, the incidence of severe acute respiratory distress syndrome is significantly lower in the subgroup of patients with antidepressant treatment (20.6% vs. 43.2% P<0.02) as well as endotracheal intubation employment (0.0% vs. 11.7% P<0.04). The rate of deceased patients of treated-subgroup is not significantly lower than the rate of not-treated subgroup (23.5% vs. 26.4% P=0.13). CONCLUSIONS: During COVID-19 pneumonia, the production of interleukin-6 seems to be modulated in presence of antidepressant therapy. Further proofs and broader surveys are necessary.

Effectiveness of tocilizumab in hospitalized moderate-to-severe COVID-19 patients: a real-life study.

BACKGROUND: To assess the clinical effectiveness of Tocilizumab (TCZ) in moderate-to-severe hospitalized COVID-19 patients and factors associated with clinical response. METHODS: Five hundred eight inpatients with moderate-to-severe SARS-CoV-2 infection were enrolled. TCZ effect in addition to standard medical therapy was evaluated in terms of death during hospital stay. Unadjusted and adjusted risk of mortality for TCZ treated patients versus TCZ untreated ones was estimated using robust Cox regression model. We considered the combination of TCZ and ICU as time-dependent exposure and created a model using duplication method to assess the TCZ effect in very severe COVID-19 patients. RESULTS: TCZ reduced death during hospital stay in the unadjusted model (HR 0.54, 95%CI 0.33-0.88) and also in the adjusted model, although with loss of statistical significance (HR 0.72, 0.43-1.20). Better effectiveness was observed in patients with low SpO2/FiO2 ratio (HR 0.35, 0.21-0.61 vs. 1.61, 0.54-4.82, P<0.05), and, without statistical significance, in patients with high CRP (HR 0.51, 0.30-0.87 vs. 0.41, 0.12-1.37, P=NS) and high IL-6 (HR 0.49, 0.29-0.82 vs. 1.00, 0.28-3.55, P=NS). TCZ was effective in patients not admitted to ICU, both in the unadjusted (HR 0.33, 0.14-0.74) and in the adjusted (HR 0.39, 0.17-0.91) model but no benefit was observed in critical ICU-admitted patients both in the unadjusted (HR 0.66, 0.37-1.15) and in the adjusted model (HR 0.95, 0.54-1.68). CONCLUSIONS: Our real-life study suggests clinical efficacy of TCZ in moderate-to-severe COVID-19 patients but not in end-stage disease. Thus, to enhance TCZ effectiveness, patients should be selected before grave compromise of clinical conditions.

Lobular panniculitis with small vessel vasculitis associated with ulcerative colitis.

We report a rare case of lobular panniculitis with small vessel vasculitis, presenting with fever, cutaneous lesions, and systemic manifestations involving the visceral fat and associated with ulcerative colitis. The patient was treated with cyclophosphamide and prednisolone, which successfully cured the systemic disease, with resolution of the inflammatory infiltrates.

Epidemiology of systemic sclerosis: a multi-database population-based study in Tuscany (Italy).

BACKGROUND: Systemic Sclerosis (SSc) is a chronic autoimmune disease with a complex pathogenesis that includes vascular injury, abnormal immune activation, and tissue fibrosis. We provided a complete epidemiological characterization of SSc in the Tuscany region (Italy), considering prevalence and incidence, survival, comorbidities and drug prescriptions, by using a multi-database population-based approach. Cases of SSc diagnosed between 1st January 2003 and 31st December 2017 among residents in Tuscany were collected from the population-based Rare Diseases Registry of Tuscany. All cases were linked to regional health and demographic databases to obtain information about vital statistics, principal causes of hospitalization, complications and comorbidities, and drug prescriptions. RESULTS: The prevalence of SSc in Tuscany population resulted to be 22.2 per 100,000, with the highest prevalence observed for the cases aged ≥ 65 years (33.2 per 100,000, CI 95% 29.6-37.3). In females, SSc was predominant (86.7% on the total) with an overall sex ratio F/M of 6.5. Nevertheless, males presented a more severe disease, with a lower survival and significant differences in respiratory complications and metabolic comorbidities. Complications and comorbidities such as pulmonary involvement (HR = 1.66, CI 95% 1.17-2.35), congestive heart failure (HR = 2.76, CI 95% 1.80-4.25), subarachnoid and intracerebral haemorrhage (HR = 2.33, CI 95% 1.21-4.48) and malignant neoplasms (HR = 1.63, CI 95% 1.06-2.52), were significantly associated to a lower survival, also after adjustment for age, sex and other SSc-related complications. Disease-modifying antirheumatic drugs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors were the drugs with the more increasing prevalence of use in the 2008-2017 period. CONCLUSIONS: The multi-database approach is important in the investigation of rare diseases where it is often difficult to provide accurate epidemiological indicators. A population-based registry can be exploited in synergy with health databases, to provide evidence related to disease outcomes and therapies and to assess the burden of disease, relying on a large cohort of cases. Building an integrated archive of data from multiple databases linking a cohort of patients to their comorbidities, clinical outcomes and survival, is important both in terms of treatment and prevention.

Characterization of lymphocyte subsets in ascitic fluid and peripheral blood of decompensated cirrhotic patients with chronic hepatitis C and alcoholic liver disease: A pivotal study.

Hepatitis C virus and alcoholic liver disease are major causes of chronic liver diseases worldwide. Little is known about differences between chronic hepatitis C and alcoholic liver disease in terms of lymphocytes' sub-population. Aim of the present study was to compare the sub-populations of lymphocytes in both ascitic compartment and peripheral blood in patients with decompensated liver cirrhosis due to chronic hepatitis C and alcoholic liver disease. Patients with decompensated liver cirrhosis due to hepatitis C virus or alcoholic liver disease evaluated from April 2014 to October 2016 were enrolled. Whole blood and ascitic fluid samples were stained with monoclonal antibodies specific for human TCRɑß, TCRɣδ, CD3, CD4, CD8, CD19, CCR6, CD16, CD56, CD25, HLA-DR, Vɑ24. Sixteen patients with decompensated liver cirrhosis were recruited (9 with hepatitis C virus and 7 with alcoholic liver disease). In ascitic fluid, the percentage of both CD3+CD56- and CD3+CD56+iNKT cells resulted higher in hepatitis C virus patients than in alcoholic liver disease patients (1.82 ± 0.35% vs 0.70 ± 0.42% (p < 0.001) and 1.42 ± 0.35% vs 0.50 ± 0.30% (p < 0.001), respectively). Conversely, in peripheral blood samples, both CD3+CD56- and CD3+CD56+iNKT cells resulted significantly higher in alcoholic liver disease than in hepatitis C virus patients (4.70 ± 2.69% vs 1.50 ± 1.21% (p < 0.01) and 3.10 ± 1.76% vs 1.00 ± 0.70% (p < 0.01), respectively). Both elevation of iNKT cells in ascitic fluid and reduction in peripheral blood registered in hepatitis C virus but not in alcoholic liver disease patients might be considered indirect signals of tissutal translocation. In conclusion, we described relevant differences between the two groups. Alcoholic liver disease patients displayed lower number of CD3+CD4+ cells and a higher percentage of CD3-CD16+, Vα24+CD3+CD56- and Vα24+CD3+CD56+iNKT cells in ascitic fluid than hepatitis C virus positive subjects. Further studies might analyze the role of immune cells in the vulnerability toward infections and detect potential targets for new treatments especially for alcoholic liver disease patients.

Prompt Predicting of Early Clinical Deterioration of Moderate-to-Severe COVID-19 Patients: Usefulness of a Combined Score Using IL-6 in a Preliminary Study.

BACKGROUND: The early identification of patients at risk of clinical deterioration is of interest considering the timeline of COVID-19 after the onset of symptoms. OBJECTIVE: The aim of our study was to evaluate the usefulness of testing serum IL-6 and other serological and clinical biomarkers, to predict a short-term negative clinical course of patients with noncritical COVID-19. METHODS: A total of 208 patients with noncritical COVID-19 pneumonia at admission were consecutively enrolled. Clinical and laboratory findings obtained on admission were analyzed by using survival analysis and stepwise logistic regression for variable selection. Three-day worsening as outcome in a logistic model to generate a prognostic score was used. RESULTS: Clinical worsening occurred in 63 patients (16 = died; 39 = transferred to intensive care unit; 8 worsening of respiratory failure). Forty-five of them worsened within 3 days after admission. The risk of clinical worsening was progressively enhanced along with increasing quartiles of IL-6 levels. Multivariate analysis showed that IL-6 (P = .005), C-reactive protein (CRP) (P = .003), and SaO2/FiO2 (P = .014) were the best predictors for clinical deterioration in the first 3 days after admission. The combined score yielded an area under the curve = 0.88 (95% confidence interval: 0.83-0.93). A nomogram predicting the probability of 3-day worsening was generated. The score also showed good performance for 7-day and 14- or 21-day worsening and in predicting death occurring during all the follow-up. CONCLUSIONS: Combining IL-6, CRP, and SaO2/FiO2 in a score may help clinicians to identify on admission those patients with COVID-19 who are at high risk for a further 3-day clinical deterioration.

Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent.

BACKGROUNDCoronavirus disease 19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. Antiviral immune response is crucial to achieve pathogen clearance; however, in some patients an excessive and aberrant host immune response can lead to an acute respiratory distress syndrome. The comprehension of the mechanisms that regulate pathogen elimination, immunity, and pathology is essential to better characterize disease progression and widen the spectrum of therapeutic options.METHODSWe performed a flow cytometric characterization of immune cell subsets from 30 patients with COVID-19 and correlated these data with clinical outcomes.RESULTSPatients with COVID-19 showed decreased numbers of circulating T, B, and NK cells and exhibited a skewing of CD8+ T cells toward a terminally differentiated/senescent phenotype. In agreement, CD4+ T and CD8+ T, but also NK cells, displayed reduced antiviral cytokine production capability. Moreover, a reduced cytotoxic potential was identified in patients with COVID-19, particularly in those who required intensive care. The latter group of patients also showed increased serum IL-6 levels that inversely correlated to the frequency of granzyme A-expressing NK cells. Off-label treatment with tocilizumab restored the cytotoxic potential of NK cells.CONCLUSIONThe association between IL-6 serum levels and the impairment of cytotoxic activity suggests the possibility that targeting this cytokine may restore antiviral mechanisms.FUNDINGThis study was supported by funds from the Department of Experimental and Clinical Medicine of University of Florence (the ex-60% fund and the "Excellence Departments 2018-2022 Project") derived from Ministero dell'Istruzione, dell'Università e della Ricerca (Italy).

Reflex testing of speckled cytoplasmic patterns observed in routine ANA HEp-2 indirect immunofluorescence with a multiplex anti-synthetase dot-blot assay: a multicentric pilot study.

Immunofluorescence on HEp2-cells is the standard diagnostic assay for the detection of anti-nuclear antibodies (ANA). Cytoplasmic speckled patterns are a common finding, and are associated with various antibodies, including anti-synthetase antibodies. However, classic ENA testing generally identifies only anti-Jo-1. Moreover, anti-synthetase syndrome is increasingly recognized as a pleomorphic entity, possibly presenting as isolated arthritis or interstitial lung disease. Sera referred for routine ANA testing were selected on the basis of the presence of a fine dense speckled cytoplasmic pattern (254 samples) and compared to control sera with negative cytoplasm (239 samples). All 493 samples were tested with a commercial synthetase profile dot-blot (D TEK - Alphadia-Alifax) including anti-Jo1, anti-PL7, anti-PL12, anti-EJ, anti-OJ, anti-KS, anti-ZO, anti-HA, anti-SRP, and anti-Ribosome P0. Retrospective clinical data was searched for positive patients. Dot-blot identified 18/254 (7.1%) positive sera in the samples with a cytoplasmic fluorescence pattern and 4/239 (1.7%) in the control group (χ2 = 8.4627; p = 0.003625). Blot intensity was more intense in samples with concordant cytoplasmic staining (cytoplasmic negative 27 ± 12.4; cytoplasmic positive 53.9 27 ± 27.7; p = 0.0027). In the positive samples, 8/18 had a highly compatible diagnosis (myositis, interstitial lung disease, arthritis), 7/18 an uncharacterized connective tissue disease, and 3 a diagnosis not associated with the presence of anti-synthetase antibodies. We evaluated the performance of a dot-blot assay for anti-cytoplasmic antibodies in a serologic cohort presenting a cytoplasmic speckled pattern found during routine ANA testing. This algorithm enabled the identification of a significant quota of patients with rare anti-synthetase antibodies and an incomplete or atypical clinical picture. Reflex testing strategies of speckled cytoplasmic patterns with multiplex assays containing cytoplasm-specific antigens, as opposed to standard ENA testing, may yield important data and for this reason should be implemented in routine ANA testing.

Uveitis in autoimmune hepatitis: a case report.

In this case report we describe for the first time an association between autoimmune hepatitis (AIH) and uveitis, without any doubts about other possible etiologies, such as HCV, since all the old reports describe the association of AIH with iridocyclitis before tests for HCV-related hepatitis could be available. A 38-year-old businessman with abnormal liver function tests and hyperemia of the bulbar conjunctiva was admitted to the hospital. Six years before admission, the patient presented with persistent fever, arthralgias, conjunctival hyperemia, leukocytosis and increased ESR, referred to acute rheumatic fever. The presence of systemic diseases, most commonly associated with uveitis, was investigated without results and the patient was then treated with topical corticosteroids. His symptoms resolved. A test for anti-nuclear antibodies was positive, at a titre of 1:320, with a speckled and nucleolar staining pattern. Liver ultrasound showed mild hepatomegaly with an increased echostructure of the liver. Percutaneous liver biopsy was performed under ultrasound assistance. Histological examination showed necroinflammation over the portal, periportal and lobular areas, fibrotic portal tracts, with periportal fibrosis and occasional portal-to-portal bridgings, but intact hepatic architecture. Some hepatocytes showed barely discernible granules of hemosiderin in the lobular area. Bile ductules had not any significant morphological alterations. METAVIR score was A2-F3, according to the modified HAI grading/fibrosis staging. The patient was diagnosed to have AIH with mild activity and fibrosis and was discharged on 25 mg prednisone, entering clinical and biochemical remission, further confirming diagnosis. After discharge the patient continued to have treatment with corticosteroids as an outpatient at a dose of 5 mg. On January 2002 the patient was readmitted to the hospital. A test for anti-nuclear antibodies was positive, at a titre of 1:320, with a speckled and nucleolar staining pattern. Anti-smooth muscle antibody test was also positive (1:160), while anti-LKM antibodies were negative. Ophthalmologic examination revealed inflammatory cells and proteinaceous flare in the anterior chamber of the left eye, and a stromal lesion in the cornea. He was maintained on immunosuppressive therapy (5 mg prednisone plus topical antibiotic therapy for two weeks) and then discharged. A complete remission of the symptoms was registered on follow-up. At present (July 2005), the patient is on prednisone (5 mg) and has no symptoms. Liver function tests are also within the normal range.

Human TH1 and TH2 Subsets.

Human CD4+ T cell clones secreting different patterns of cytokines similar to TH1 and TH2 cells described in mice have been demonstrated. These human TH1 and TH2 clones are produced in response to different antigens and exhibit distinct functional properties. TH1 clones are produced in response to intracellular bacteria and viruses, do not provide help for IgE production and possess cytolytic potential, whereas TH2 clones are produced in response to allergens and helminth components, provide optimal help for IgM, IgG, IgA and IgE synthesis, and lack cytolytic potential. The cytokine profile of 'natural' immunity evoked by intracellular parasites and viruses through the activation of macrophages and NK cells probably determines the phenotype of the subsequent specific immune (TH1) response. TH1 cells are not only involved in the protection against intracellular parasites but also play a role in the genesis of some organ-specific autoimmune diseases, such as Hashimoto's thyroiditis. In contrast, TH2 cells are responsible for the initiation of the allergic cascade.

Kounis syndrome (allergic acute coronary syndrome): different views in allergologic and cardiologic literature.

The clinical picture of myocardial ischemia accompanying allergic reactions is defined in the cardiologic literature as Kounis syndrome (KS) or allergic angina/myocardial infarction. In PubMed, a search for "Kounis syndrome", "allergic angina" or "allergic myocardial infarction" retrieves more than 100 results (among case reports, case series and reviews), most of which are published in cardiology/internal medicine/emergency medicine journals. In allergologic literature, heart involvement during anaphylactic reactions is well documented, but Kounis syndrome is hardly mentioned. Single case reports and small case series of angina triggered by allergic reactions have been reported for many years, and involvement of histamine and others mast cell mediators in the pathogenesis of coronary spasm has long been hypothesized, but the existence of an allergic acute coronary syndrome (ACS) is still questioned in the allergologic scientific community. Putative mechanisms of an allergic acute coronary syndrome include coronary spasm or heart tissue-resident mast cell activation (precipitating coronary spasm or inducing plaque rupture and coronary or stent thrombosis) due to systemic increase of allergic mediators, or heart tissue-resident mast cell activation by local stimuli. Indeed, the pathogenic mechanism of an ACS after an allergic insult might be related to direct effects of mast cell mediators on the myocardium and the atherosclerotic plaque, or to exacerbation of preexisting disease by the hemodynamic stress of the acute allergic/anaphylactic reaction. Which of these mechanisms is most important is still unclear, and this review outlines current views in the cardiologic and allergologic literature.