Cardio-Oncoimmunology: Cardiac Toxicity, Cardiovascular Hypersensitivity, and Kounis Syndrome.

Cancer therapy can result in acute cardiac events, such as coronary artery spasm, acute myocardial infarction, thromboembolism, myocarditis, bradycardia, tachyarrhythmias, atrio-ventricular blocks, QT prolongation, torsades de pointes, pericardial effusion, and hypotension, as well as chronic conditions, such as hypertension, and systolic and diastolic left ventricular dysfunction presenting clinically as heart failure or cardiomyopathy. In cardio-oncology, when referring to cardiac toxicity and cardiovascular hypersensitivity, there is a great deal of misunderstanding. When a dose-related cardiovascular side effect continues even after the causative medication is stopped, it is referred to as a cardiotoxicity. A fibrotic response is the ultimate outcome of cardiac toxicity, which is defined as a dose-related cardiovascular adverse impact that lasts even after the causative treatment is stopped. Cardiotoxicity can occur after a single or brief exposure. On the other hand, the term cardiac or cardiovascular hypersensitivity describes an inflammatory reaction that is not dose-dependent, can occur at any point during therapy, even at very low medication dosages, and can present as Kounis syndrome. It may also be accompanied by anti-drug antibodies and tryptase levels. In this comprehensive review, we present the current views on cardiac toxicity and cardiovascular hypersensitivity, together with the reviewed cardiac literature on the chemotherapeutic agents inducing hypersensitivity reactions. Cardiac hypersensitivity seems to be the pathophysiologic basis of coronary artery spasm, acute coronary syndromes such as Kounis syndrome, and myocarditis caused by cancer therapy.

Effects of COVID-19 Infection and Vaccination on the Female Reproductive System: A Narrative Review

Several studies and research papers have been published to elucidate and understand the mechanism of the coronavirus disease 2019 (COVID-19) pandemic and its long-term effects on the human body. COVID-19 affects a number of organs, including the female reproductive system. However, less attention has been given to the effects of COVID-19 on the female reproductive system due to their low morbidity. The results of studies investigating the relationship between COVID-19 infection and ovarian function in women of reproductive age have shown the harmless involvement of COVID-19 infection. Several studies have reported the involvement of COVID-19 infection in oocyte quality, ovarian function, and dysfunctions in the uterine endometrium and the menstrual cycle. The findings of these studies indicate that COVID-19 infection negatively affects the follicular microenvironment and dysregulate ovarian function. Although the COVID-19 pandemic and female reproductive health have been studied in humans and animals, very few studies have examined how COVID-19 affects the female reproductive system. The objective of this review is to summarize the current literature and categorize the effects of COVID-19 on the female reproductive system, including the ovaries, uterus, and hormonal profiles. The effects on oocyte maturation, oxidative stress, which causes chromosomal instability and apoptosis in ovaries, in vitro fertilization cycle, high-quality embryos, premature ovarian insufficiency, ovarian vein thrombosis, hypercoagulable state, women's menstrual cycle, the hypothalamus-pituitary-ovary axis, and sex hormones, including estrogen, progesterone, and the anti-Müllerian hormone, are discussed in particular.

Blood Transfusion Components Inducing Severe Allergic Reactions: The First Case of Kounis Syndrome Induced by Platelet Transfusion.

Kounis syndrome is a multisystem and multidisciplinary disease affecting the circulatory system that can be manifested as spasm and thrombosis. It can occur as allergic, hypersensitivity, anaphylactic, or anaphylactoid reactions associated with the release of inflammatory mediators from mast cells and from other interrelated and interacting inflammatory cells, including macrophages and lymphocytes. A platelet subset with high- and low-affinity IgE surface receptors is also involved in this process. Whereas the heart, and particularly the coronary arteries, constitute the primary targets of inflammatory mediators, the mesenteric, cerebral, and peripheral arteries are also vulnerable. Kounis syndrome is caused by a variety of factors, including drugs, foods, environmental exposure, clinical conditions, stent implantation, and vaccines. We report a unique case of a 60-year-old male with a past medical history of allergy to human albumin, alcoholic cirrhosis, and esophageal varices, who was admitted due to multiple episodes of hematemesis. Due to low hemoglobin levels, he was transfused with 3 units of red blood cells and fresh frozen plasma without any adverse reactions. On the third day of hospitalization, severe thrombocytopenia was observed and transfusion of platelets was initiated. Immediately following platelet infusion, the patient developed chest discomfort, skin signs of severe allergic reaction, and hemodynamic instability. The electrocardiogram revealed ST segment elevation in the inferior leads. Given the strong suspicion of Kounis syndrome/allergic coronary spasm, the patient was treated with anti-allergic treatment only, without any anti-platelet therapy. The clinical status of the patient gradually improved and the electrocardiographic changes reverted to normal. Based on these findings, Kounis hypersensitivity-associated acute coronary syndrome, specifically, type I Kounis syndrome, was diagnosed. Although platelet transfusion can be a life-saving therapy, each blood transfusion carries a substantial risk of adverse reactions. The aims of this report are to expand the existing knowledge of patient responses to blood transfusion and provide information on the incidence of various severe transfusion reactions to all blood components and especially to platelets. To the best of our knowledge, Kounis syndrome induced by platelet transfusionhas never been previously reported. Hypersensitivity to platelet external membrane glycoproteins in an atopic patient seems to be the possible etiology. Despite that Kounis syndrome remains an under-diagnosed clinical entity in everyday practice, it should always be considered in the differential diagnosis of acute coronary syndromes.

The Effect of Long COVID-19 Infection and Vaccination on Male Fertility; A Narrative Review.

Earlier research has suggested that the male reproductive system could be particularly vulnerable to SARS-CoV-2 (COVID-19) infection, and infections involving this novel disease not only pose serious health threats but could also cause male infertility. Data from multi-organ research during the recent outbreak indicate that male infertility might not be diagnosed as a possible consequence of COVID-19 infection. Several review papers have summarized the etiology factors on male fertility, but to date no review paper has been published defining the effect of COVID-19 infection on male fertility. Therefore, the aim of this study is to review the published scientific evidence regarding male fertility potential, the risk of infertility during the COVID-19 pandemic, and the impact of COVID-19 vaccination on the male reproductive system. The effects of COVID-19 infection and the subsequent vaccination on seminal fluid, sperm count, sperm motility, sperm morphology, sperm viability, testes and sex hormones are particularly reviewed.

COVID-19 Disease, Women's Predominant Non-Heparin Vaccine-Induced Thrombotic Thrombocytopenia and Kounis Syndrome: A Passepartout Cytokine Storm Interplay.

Coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) constitute one of the deadliest pandemics in modern history demonstrating cardiovascular, gastrointestinal, hematologic, mucocutaneous, respiratory, neurological, renal and testicular manifestations and further complications. COVID-19-induced excessive immune response accompanied with uncontrolled release of cytokines culminating in cytokine storm seem to be the common pathogenetic mechanism of these complications. The aim of this narrative review is to elucidate the relation between anaphylaxis associated with profound hypotension or hypoxemia with pro-inflammatory cytokine release. COVID-19 relation with Kounis syndrome and post-COVID-19 vaccination correlation with heparin-induced thrombocytopenia with thrombosis (HITT), especially serious cerebral venous sinus thrombosis, were also reviewed. METHODS: A current literature search in PubMed, Embase and Google databases was performed to reveal the pathophysiology, prevalence, clinical manifestation, correlation and treatment of COVID-19, anaphylaxis with profuse hypotension, Kounis acute coronary syndrome and thrombotic events post vaccination. RESULTS: The same key immunological pathophysiology mechanisms and cells seem to underlie COVID-19 cardiovascular complications and the anaphylaxis-associated Kounis syndrome. The myocardial injury in patients with COVID-19 has been attributed to coronary spasm, plaque rupture and microthrombi formation, hypoxic injury or cytokine storm disposing the same pathophysiology with the three clinical variants of Kounis syndrome. COVID-19-interrelated vaccine excipients as polysorbate, polyethelene glycol (PEG) and trometamol constitute potential allergenic substances. CONCLUSION: Better acknowledgement of the pathophysiological mechanisms, clinical similarities, multiorgan complications of COVID-19 or other viral infections as dengue and human immunodeficiency viruses along with the action of inflammatory cells inducing the Kounis syndrome could identify better immunological approaches for prevention, treatment of the COVID-19 pandemic as well as post-COVID-19 vaccine adverse reactions.

Allergic Reactions to Current Available COVID-19 Vaccinations: Pathophysiology, Causality, and Therapeutic Considerations.

Vaccines constitute the most effective medications in public health as they control and prevent the spread of infectious diseases and reduce mortality. Similar to other medications, allergic reactions can occur during vaccination. While most reactions are neither frequent nor serious, anaphylactic reactions are potentially life-threatening allergic reactions that are encountered rarely, but can cause serious complications. The allergic responses caused by vaccines can stem from activation of mast cells via Fcε receptor-1 type I reaction, mediated by the interaction between immunoglobulin E (IgE) antibodies against a particular vaccine, and occur within minutes or up to four hours. The type IV allergic reactions initiate 48 h after vaccination and demonstrate their peak between 72 and 96 h. Non-IgE-mediated mast cell degranulation via activation of the complement system and via activation of the Mas-related G protein-coupled receptor X2 can also induce allergic reactions. Reactions are more often caused by inert substances, called excipients, which are added to vaccines to improve stability and absorption, increase solubility, influence palatability, or create a distinctive appearance, and not by the active vaccine itself. Polyethylene glycol, also known as macrogol, in the currently available Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines, and polysorbate 80, also known as Tween 80, in AstraZeneca and Johnson & Johnson COVID-19 vaccines, are excipients mostly incriminated for allergic reactions. This review will summarize the current state of knowledge of immediate and delayed allergic reactions in the currently available vaccines against COVID-19, together with the general and specific therapeutic considerations. These considerations include: The incidence of allergic reactions and deaths under investigation with the available vaccines, application of vaccination in patients with mast cell disease, patients who developed an allergy during the first dose, vasovagal symptoms masquerading as allergic reactions, the COVID-19 vaccination in pregnancy, deaths associated with COVID-19 vaccination, and questions arising in managing of this current ordeal. Careful vaccine-safety surveillance over time, in conjunction with the elucidation of mechanisms of adverse events across different COVID-19 vaccine platforms, will contribute to the development of a safe vaccine strategy. Allergists' expertise in proper diagnosis and treatment of allergic reactions is vital for the screening of high-risk individuals.

A novel method of brainstem auditory evoked potentials using complex verbal stimuli.

BACKGROUND: The click and tone-evoked auditory brainstem responses are widely used in clinical practice due to their consistency and predictability. More recently, the speech-evoked responses have been used to evaluate subcortical processing of complex signals, not revealed by responses to clicks and tones. AIMS: Disyllable stimuli corresponding to familiar words can induce a pattern of voltage fluctuations in the brain stem resulting in a familiar waveform, and they can yield better information about brain stem nuclei along the ascending central auditory pathway. MATERIALS AND METHODS: We describe a new method with the use of the disyllable word "baba" corresponding to English "daddy" that is commonly used in many other ethnic languages spanning from West Africa to the Eastern Mediterranean all the way to the East Asia. RESULTS: This method was applied in 20 young adults institutionally diagnosed as dyslexic (10 subjects) or light dyslexic (10 subjects) who were matched with 20 sex, age, education, hearing sensitivity, and IQ-matched normal subjects. The absolute peak latencies of the negative wave C and the interpeak latencies of A-C elicited by verbal stimuli "baba" were found to be significantly increased in the dyslexic group in comparison with the control group. CONCLUSIONS: The method is easy and helpful to diagnose abnormalities affecting the auditory pathway, to identify subjects with early perception and cortical representation abnormalities, and to apply the suitable therapeutic and rehabilitation management.

Brainstem auditory evoked potentials with the use of acoustic clicks and complex verbal sounds in young adults with learning disabilities.

PURPOSE AND BACKGROUND: Acoustic signals are transmitted through the external and middle ear mechanically to the cochlea where they are transduced into electrical impulse for further transmission via the auditory nerve. The auditory nerve encodes the acoustic sounds that are conveyed to the auditory brainstem. Multiple brainstem nuclei, the cochlea, the midbrain, the thalamus, and the cortex constitute the central auditory system. In clinical practice, auditory brainstem responses (ABRs) to simple stimuli such as click or tones are widely used. Recently, complex stimuli or complex auditory brain responses (cABRs), such as monosyllabic speech stimuli and music, are being used as a tool to study the brainstem processing of speech sounds. We have used the classic 'click' as well as, for the first time, the artificial successive complex stimuli 'ba', which constitutes the Greek word 'baba' corresponding to the English 'daddy'. PATIENTS AND METHODS: Twenty young adults institutionally diagnosed as dyslexic (10 subjects) or light dyslexic (10 subjects) comprised the diseased group. Twenty sex-, age-, education-, hearing sensitivity-, and IQ-matched normal subjects comprised the control group. Measurements included the absolute latencies of waves I through V, the interpeak latencies elicited by the classical acoustic click, the negative peak latencies of A and C waves, as well as the interpeak latencies of A-C elicited by the verbal stimulus 'baba' created on a digital speech synthesizer. RESULTS: The absolute peak latencies of waves I, III, and V in response to monoaural rarefaction clicks as well as the interpeak latencies I-III, III-V, and I-V in the dyslexic subjects, although increased in comparison with normal subjects, did not reach the level of a significant difference (p<0.05). However, the absolute peak latencies of the negative wave C and the interpeak latencies of A-C elicited by verbal stimuli were found to be increased in the dyslexic group in comparison with the control group (p=0.0004 and p=0.045, respectively). In the subgroup consisting of 10 patients suffering from 'other learning disabilities' and who were characterized as with 'light' dyslexia according to dyslexia tests, no significant delays were found in peak latencies A and C and interpeak latencies A-C in comparison with the control group. CONCLUSIONS: Acoustic representation of a speech sound and, in particular, the disyllabic word 'baba' was found to be abnormal, as low as the auditory brainstem. Because ABRs mature in early life, this can help to identify subjects with acoustically based learning problems and apply early intervention, rehabilitation, and treatment. Further studies and more experience with more patients and pathological conditions such as plasticity of the auditory system, cochlear implants, hearing aids, presbycusis, or acoustic neuropathy are necessary until this type of testing is ready for clinical application.

Auditory brainstem responses in dyslexia: comparison between acoustic click and verbal stimulus events.

OBJECTIVES: This study examined the use of auditory brainstem response (ABR) by classic clicks and verbal stimuli in young dyslexic adults to identify latency abnormalities. METHODS: Subjects included 10 dyslexic adults and 10 age-, sex-, IQ-, education-, and hearing sensitivity-matched normal subjects. Both groups had normal auditory status. Measurements included the absolute latencies of waves I through V; the interpeak latencies I-III, III-V, and I-V elicited by acoustic click; and the negative peak latencies of A and B waves, as well as the interpeak latencies of A-B elicited by the verbal stimulus "ma," created on a digital speech synthesizer. RESULTS: The measured latencies and interpeak latencies in response to both clicks and verbal stimuli were found delayed in eight dyslexic subjects, although they did not reach the level of significant difference. However, two dyslexic subjects had significantly delayed peak and interpeak latencies elicited by verbal stimuli. CONCLUSIONS: There are dyslexic subjects who may have abnormalities in acoustic representation of a speech sound as low as the auditory brainstem, as elicited by the verbal stimulus "ma."