While it took decades to arrive to a conclusion that ferritin is more than an indicator of iron storage level, it took a short period of time through the COVID-19 pandemic to wonder what the reason behind high levels of ferritin in patients with severe COVID-19 might be. Unsurprisingly, acute phase reactant was not a satisfactory explanation. Moreover, the behavior of ferritin in patients with severe COVID-19 and the subsequent high mortality rates in patients with high ferritin levels necessitated further investigations to understand the role of ferritin in the diseases. Ferritin was initially described to accompany various acute infections, both viral and bacterial, indicating an acute response to inflammation. However, with the introduction of the hyperferritinemic syndrome connecting four severe pathological conditions such as adult-onset Still's disease, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and septic shock added another aspect of ferritin where it could have a pathogenetic role rather than an extremely elevated protein only. In fact, suggesting that COVID-19 is a new member in the spectrum of hyperferritinemic syndrome besides the four mentioned conditions could hopefully direct further search on the pathogenetic role of ferritin. Doubtlessly, improving our understanding of those aspects of ferritin would enormously contribute to better coping with severe diseases in terms of treatment and prevention of complications. The origin, history, importance, and the advances of searching the role of ferritin in various pathological and clinical processes are presented hereby in our article. In addition, the implications of ferritin in COVID-19 are addressed.

Despite their proven efficacy and huge contribution to the health of humankind, vaccines continue to be a source of concern for some individuals around the world. Vaccinations against COVID-19 increased the number of distressed people and intensified their distrust, particularly as the pandemic was still emerging and the populations were encouraged to be vaccinated under various slogans like “back to normal life” and “stop coronavirus”, goals which are still to be achieved. As fear of vaccination-related adverse events following immunization (AEFIs) is the main reason for vaccine hesitancy, we reviewed immune and autoimmune AEFIs in particular, though very rare, as the most worrisome aspect of the vaccines. Among others, autoimmune AEFIs of the most commonly administered COVID-19 vaccines include neurological ones such as Guillain-Barre syndrome, transverse myelitis, and Bell’s palsy, as well as myocarditis. In addition, the newly introduced notion related to COVID-19 vaccines, “vaccine-induced immune thrombotic thrombocytopenia/vaccine-induced prothrombotic immune thrombotic thrombocytopenia” (VITT/VIPITT)”, is of importance as well. Overviewing recent medical literature while focusing on the major immune and autoimmune AEFIs, demonstrating their rate of occurrence, presenting the cases reported, and their link to the specific type of COVID-19 vaccines represented the main aim of our work. In this narrative review, we illustrate the different vaccine types in current use, their associated immune and autoimmune AEFIs, with a focus on the 3 main COVID-19 vaccines (BNT162b2, mRNA-1273, and ChAdOx1). While the rate of AEFIs is extremely low, addressing the issue in this manner, in our opinion, is the best strategy for coping with vaccine hesitancy.

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Since vaccines are in fact manufactured chemical compounds such as drugs, the appearance of side effects following their use is not surprising. Similarly, as the main goal of vaccines is to stimulate the immune system bringing out the production of protective antibodies, autoimmune-related side effects as a consequence of increased immune activity do not seem irrational. Fortunately, the rate of such side effects is low; however, the importance of reporting adverse events following vaccinations, understanding the mechanisms behind their appearance, making early diagnosis, and appropriate treatment cannot be overemphasized. In fact, autoimmune-related side effects of vaccines, particularly those based on adjuvants, were reported long before the introduction of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Nevertheless, ASIA gathered and united the side effects of vaccines under one title, a step which helped organize the research and call for better immune stimulators than adjuvants. New technologies and methods of making vaccines were clearly noticed during the pandemic of COVID-19 after the introduction of mRNA-based vaccines. In our current paper, we introduce the notion of side effects to vaccines, particularly those of autoimmune nature, the mechanisms of ASIA, and the main vaccines linked with the syndrome including the recent COVID-19 vaccines. The transition from side effects to ASIA is the main idea behind our work.

Summary Adjuvants, as the name indicates, are adjoined material aimed to assist in functioning as when added to vaccines they are meant to boost the effect and strongly stimulate the immune system. The response of the immune system can be unpredictable, and the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was developed to address possible adverse reactions of an autoimmune and inflammatory type that may be caused by adjuvants. While ASIA, as a syndrome, was coined and defined in 2011; reports describing patients with vague and nonspecific clinical symptoms following vaccinations appeared much earlier. In other words, ASIA came to define, arrange, and unite the variety of symptoms, related to autoimmunity, caused not by the vaccine itself, rather by the adjuvant part of the vaccine such as aluminum, among others. Accordingly, the introduction of ASIA enabled better understanding, proper diagnosis, and early treatment of the disorder. Furthermore, ASIA was shown to be associated with almost all body systems and various rheumatic and autoimmune diseases such as SLE, APS, and systemic sclerosis. In addition, the correlation between COVID-19 and ASIA was noticed during the pandemic. In this review, we summarized the reported effects of adjuvants and medical literature before and after ASIA was defined, the several ways ASIA can manifest and impact different systems of the body, and the incidences of ASIA during the COVID-19 pandemic. It is important to clarify, that vaccines are among, if not the, most effective means of fighting infectious diseases however, we believe that vaccines manufacturing is not above criticism, particularly when it comes to added substances possessing a risk of side effects.