Basic Mechanisms of Multisystemic Inflammatory Syndrome and Severe Acute Respiratory Syndrome Coronavirus 2

Abstract

Multisystemic inflammatory syndrome is a condition developed by various factors such as chronic diseases, diverse body traumas, postoperative complications, and hypoxia. Within the main characteristics of this pathological condition, there is an increase in body temperature, free radicals, proinflammatory cytokines, lymphocytes, and even apoptosis. However, gravity depends on each of the organisms, its characteristics, as well as from the presence of other conditions such as overweight, obesity, and in recent years the infection has al severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), etc. With the above, it is essential to mention that the body uses several cell and molecular mechanisms to counteract the effects of inflammation for a long time. Therefore, life expectancy will depend on each patient’s genetic, metabolic, and physiological response characteristics. This chapter describes the basic mechanisms given during the development of multisystemic inflammatory syndrome.

1. Introduction

Inflammation is a pathological process characterized by injury or tissue destruction caused by various cytologic and chemical reactions and usually manifested by typical signs of pain, heat, redness, swelling, and loss of function [1]. Aggressive factors such as a blow, exposure to toxic substances, lack of oxygen, and even autoimmune diseases generate inflammation. In general, during the inflammatory process, the organism develops a homeostatic regulation response to not alter or deregulate other essential basic functions of the cells, tissues, systems, or organs near the site of inflammation [2].

In cells and tissues, inflammation in principle facilitates the activation and participation of peptides and non-peptide molecules mediating the process, such as histamine, bradykinin, eicosanoids, chemokines, platelet-activating factor, fibrin, and the complement system. Subsequently, and once the process has begun, other cellular components of a protein nature will participate, such as proinflammatory cytokines or interleukins 1, 6 (IL-1, IL-6), tumor necrosis factor (TNF), as well as other attractant molecules such as interleukins 2, 8 (IL-8). The latter will induce the lymphocyte response; continuing with the inflammatory process, interleukin 3 (IL-3), granulocyte, and macrophage colony-stimulating factor (GM-CSF) will facilitate cell mitosis in the bone marrow. Finally, and in general, the inflammatory process is suppressed with interleukin 10 (IL-10) participation and transforming growth factor beta (TGF-β) [3].

In addition to the participation of the molecules mentioned above, other processes involve the increase of vascular diameter, thus facilitating blood flow to the affected area, followed by the elevation of temperature and redness. Subsequently, vascular permeability will increase, enabling the passage of fluid and immunoglobulin proteins that will generate edema. Finally, if the response to the acute inflammation is successful, the factor that caused the inflammatory process will be effectively eliminated and repaired; however, if the cell is functional or the damage is limited, the inflammation will continue and become a chronic or systemic event [4].

The main characteristic of systemic inflammation is the increase in the levels of inflammatory cytokines, as well as a more significant infiltration of macrophages to peripheral tissues. In this regard, this type of inflammation is considered a low grade, which is characteristic of maintaining the functionality of the affected tissue, for example, the inflammation present in diseases such as obesity, cardiometabolic, and other metabolic disorders, etc. [5].

On the other hand, there are also inflammatory processes such as Multisystemic Inflammatory Syndrome (MIS). The researchers detected this rare inflammation in children and adolescents infected with SARS-CoV-2; however, this condition has also developed in adults infected with SARS-CoV-2. The main characteristic of MIS is the development of inflammation in the whole organism. Therefore, the inflammatory process is in external and internal areas such as the heart, digestive system, skin, and brain. Moreover, this syndrome is more frequent in children than adults, who have been shown to recover faster from generalized inflammation and may not have severe cardiac complications [6].

2. Cellular mechanisms of inflammation

In the organism, the inflammatory process is complex because the factor that triggers it can be biological, chemical, or physical. As mentioned above, inflammation can be of acute and chronic type. The acute type has as its main characteristic the attraction of leukocytes due to the release of chemotactic molecules. The purpose of this action is to take care of the injury and specifically, the elimination of the agent that produced the activation of the inflammatory process and thus give way to regeneration or cellular repair [7].

During the acute phase, proinflammatory cytokines play a vital role. In this regard, all organism cells can synthesize and respond to these proteins, which vary in size (8–40,000 Da) and are soluble and pleiotropic. These molecules regulate other immune systems and blood-type cells’ growth and functionality. In addition, given their distribution throughout the body, they have autocrine, paracrine and endocrine communication; and are classified according to the function they perform, but in general, their role is to mediate and regulate the processes of inflammation and immunity against aggressive stimuli that interrupt the inter and intracellular communication. It is essential to mention that there are several types of cytokines and among these are lymphokines, monokines and chemokines, which are produced by lymphocytes, monocytes and leukocytes [8].

In the acute phase of inflammation, platelets and granulocytic cells such as basophils, mast cells neutrophils and eosinophils; which are activated and, in turn, produce and release a series of soluble mediators that stimulate and regulate the inflammatory response. Initially, vasodilatation occurs due to increased blood flow to the affected area with the release of histamine and serotonin, followed by the participation of various molecules such as prostaglandins E (PGE1, PGE2), vasoactive intestinal polypeptide (VIP), bradykinin, and the complement system C5a and C3a. Then vascular permeability continues and in this process, in addition to the mediators PGE2, C5a and C3a, bradyB, kinin, leukotrienes B and D (LTB, LTD), fibrin products, neutrophil peptides, platelet-activating factor (PAF) and lymphokines are added. Subsequently, there is an infiltration of neutrophils by chemotaxis with the participation of C5a, LTB4, N-Formylmethionine (F-Met) peptides, PAF, IL-8, chemokines (CXCL1,2) and chemokine ligands (CCL3,4). After this comes the phase of macrophage involvement and the participation of other mediators such as lymphokines, glycopeptide (C5a desArg), fibronectin peptides, IFN, f-Met peptides, and monocyte chemoattractant protein (MCP-1). Finally, this process has two termination pathways; the first is to resolve the event of cell damage with the participation of inhibitory factors, enzyme inactivators (αM), free radical scavengers, TGF-β and IL-10. However, the other pathway allows the release of enzymes from the lysosome, an increase in free radicals and the participation of the IL-1 family group and TNFα, which will produce chronic or systemic inflammation [7].

Unlike acute inflammation, systemic inflammation is a progressive consequence that can culminate in multiple organ failure and death. During this process, inflammation is considered a non-specific defense mechanism with evident signs such as increases in body temperature, tachycardia, leukocytosis and tachypnea; for example, these manifestations are similar to those presented by patients with pancreatitis, severe trauma, severe burns, etc. In the physiopathology of systemic inflammation, the endothelium is the organ that maintains the inflammatory process; subsequently, systemic inflammation develops when various tissues are affected, either by injury, infection, hypoxia and increased free radicals or oxidative stress. In addition, as well as the participation of several molecules in the initial event of inflammation, in the systemic process participates, the nuclear factor Kappa-Beta (FN-kB), as well as its membrane receptors activated by active macrophage cytokines, virus free radicals, bacterial proteins, lipopolysaccharides and T lymphocytes [9]. Subsequently, once receptor activation has begun within the cytoplasm, protein kinases will phosphorylate and degrade the IFN-kB alpha inhibitor. With this, the heterodimer can target the cell nucleus and facilitate the translation of cytokines and other molecules involved in systemic inflammation. Another condition is the increase of free radicals, which will initiate a chain of intracellular events that will facilitate the release of the IFN-kB inhibitor; and then develop a positive regulation of genes that generate inflammatory proteins and increased production of molecules such as TNF, IL-2, serum activator proteins, nuclear factors, interleukins IL-1, IL-6, IL-8, nitric oxide synthase, lipid peroxidation, as well as a decrease in the endogenous antioxidant system and minerals such as selenium, zinc, and angiopoietins 1, 2 [9].

In addition to the above, the demanding need for protein synthesis produces deregulated metabolic modifications. For example, the nutrients in the body are distributed to all organs and systems to combat the inflammatory process. During this process, there is an increase in gluconeogenesis, proteolysis, lipolysis, lactic acid and oxide reduction processes to keep the immune system active and efficient. Unfortunately, during this process, the endogenous antioxidant capacity is overwhelmed, and generates oxidative stress; increases cellular damage, more cytokines are released, and reduces glutathione due to liver dysfunction. As described above, the maintenance of inflammation for too long develops systemic inflammatory syndrome and multiple organ failure (9).

2.1 The SARS-CoV-2 infection and the multisystemic inflammatory syndrome

During the Coronavirus disease (COVID-19) pandemic, there were initial complications in understanding the infection process and providing adequate pharmacologic treatment. Subsequently, with the application of vaccines, deaths and severe illnesses from the infection improved; however, in post-infection, children and adults developed an unexpected and not yet fully understood adverse condition, the multisystemic inflammatory syndrome MIS. This syndrome develops inflammation in various body parts, such as the gastrointestinal tract, heart and brain. This condition in children and adolescents infected by SARS-CoV-2 was detected initially; however, MIS can also develop in adults after infection and although it tends to be rare, it is severe [6]. The clinical manifestations of MIS in children are varied and have features representative of Kawasaki disease; for example, sepsis, toxic shock syndrome (TSS) and secondary hemophagocytic lymphohistiocytosis (sHLH). It is unknown to what extent children affected by MIS have a pathophysiology similar to this disease and to what time they might respond to the typical drugs used in these conditions and efficiently treated [10].

Continuing with what has been described above and specifically for SARS-CoV-2 infection, there is infection and replication of the virus in the cells and subsequently hyperinflammation develops. As is well known, the infection process requires the presence of receptors for angiotensin-converting enzyme 2; notably, the virus evades the immune response by suppressing IFN and interleukins IL-1, IL-6 and TNFα. This results in the multiplication of the virus inside the cell and its subsequent release when the cell dies and the viral load is released into the extracellular space, disperses and infects other cells. This condition will allow the activation of monocytes, neutrophils and the adaptive immune system mediated by T lymphocytes due to cellular damage and uncontrolled systemic inflammation [10]. In addition, a representative feature of SARS-CoV-2 infection is a cytokine storm or excessive and imbalanced stimulus release, in which there is excessive release of inflammatory molecules, leading to tissue and organ dysfunction and damage. Some of the signs and symptoms of this condition occur during the second-week post-SARS-CoV-2 infection, and signs and symptoms include fever, hypotension, rash, liver dysfunction, cytopenias, etc., as well as elevated IL-6 and IL-8 and other markers of inflammation. In this sense and as a differential factor from other viruses, SARS-CoV-2 infection has moderate ferritin increases, but the cytokine storm is more severe, associated with leukocytosis [11].

In addition to the above described, the increase of inflammation develops another phenomenon called antibody-dependent potentiation; this event facilitates the capture of viral detritus bound to immune cells in Fcc receptors, resulting in viral replication and organ damage. This phenomenon resembles dengue infection, where reinfections with a different serotype develop more severe clinical pictures. In the case of SARS-CoV-2 infected patients, there is a hypothesis that indicates that antibody-dependent potentiation may be critical in the development of severe infection, and the authors suggest that the process may be triggered by prior exposure to other SARS-CoV-2 serotypes, as well as common flew virus infections [12]. Notably, clinical manifestations in patients with this potentiation process include vasculitis (vasculitis skin lesions), microthrombi in small vessels and infarcts [13]. Finally and importantly, the maintenance process of the inflammatory state and presence of SARS-CoV-2 tends to be during 4 weeks and that antibody-dependent; these conditions indicate how the development of MIS starts from a delayed inflammation process [10].

Now, of the various molecules involved in the process of hyperinflammation, there are increases in ferritin, LDH, IL-6, IL-2, IL-10, TNF-α and decreases in lymphocytes (CD4, CD8), C-reactive protein, coagulation and abnormal renal function [14]. An important aspect to consider is that in the case of children, many presented mild symptoms of the infection and were even asymptomatic; this condition may predispose them to not providing specific and timely treatment, which could facilitate the worsening and severity of the disease [15]. Given the above, it is necessary to identify those signs and symptoms that indicate that people may have a severe MIS. To this end, specialists suggest the following aspects: first, there are the classic symptoms of the cardiac manifestations, such as dilated coronary arteries; then, as a second condition, there is sepsis, cardiovascular shock, or cardiac dysfunction. Similarly, the diagnosis considers a temperature higher than 38.5°C, skin rash, conjunctivitis, peripheral edema, severe abdominal pain, and diarrhea. In addition, although it may seem obvious, respiratory distress, in this case, is not one of the main symptoms. Other signs to identify are increased levels of procalcitonin, liver transaminases and anemia, thrombocytopenia or thrombocytosis, and the other molecules involved in hyperinflammation [16, 17]. Importantly, and potentially a confounding variable, not all patients are positive for SARS-CoV-2 by PCR but are positive for IgG antibodies. This feature indicates the likely hypothesis that MIS could represent a delayed inflammatory process [10].

2.2 Multisystemic inflammatory syndrome in children and adults

Given the complications that have occurred in the SARS-CoV-2 infected population during the COVID-19 pandemic, the development of MIS has been different according to age and has been more prevalent in children. In this regard, in 2021, a systematic review shows the signs and symptoms of multisystemic inflammatory syndrome in children. The main findings indicate that the median age of the affected children was 8 years, and among the signs and symptoms present during the infection were fever of more than 5 days in 99.4%, gastrointestinal problems (abdominal pain, vomiting, diarrhea) in 85.6%, cardiovascular problems (tachycardia, hemodynamic shock, myocarditis, coronary dilatation, etc.) in 79.3%, respiratory problems in 50.3% and increases in various inflammatory markers such as c-reactive protein, IL-6, and ferritin in 79.3%, respiratory problems in 50.3% and increases in inflammatory markers such as c-reactive protein, IL-6 and ferritin. Therefore, 73.3% of the patients were in intensive care but fortunately, only 1.9% of the total number of individuals presented mortality [18].

As previously described, after four to 6 weeks of SARS-CoV-2 infection and with a probable adaptive immune response, MIS develops; however, the pathophysiology is still unclear, given the diversity of signs and symptoms in patients. However, anti-SARS-CoV-2 antibodies, multisystem inflammation, cardiovascular and abdominal problems, and fever are widespread in children older than 5 years, although most pediatric patients are between 7 and 10 years of age. In this regard, many children present with MIS 36 to 45 days after initial symptoms due to COVID-19 [19]. In contrast to children infected with SARS-CoV-2 alone, children with SARS-CoV-2 who also developed MIS had increases in IL-17, IL-10 and TNF-α, and the authors indicate that this condition may be a post-infection sequela of COVID-19 and with a higher frequency of development in African Americans and Latinos [20].

Nevertheless, in the case of adults, the MIS is also complete since the signs and symptoms differ in each patient, so it is necessary to have a good knowledge of the condition and thus be able to give the appropriate treatment. As in infants, in the case of adults, symptoms include fever, rash, conjunctivitis, myocarditis and arrhythmias, fever, diarrhea, abdominal pain, myalgia, headache and some rare symptoms such as sore throat and chest pain; and in rare cases, vascular edema, ischemic/hemorrhagic stroke, status epilepticus, mononeuritis multiplex and thyroiditis; as well as, increases in c-reactive protein, IL-6 and positive serological values for SARS-CoV2 by serology or RT-PCR [21].

Therefore, the pathophysiology of MIS in adults is also still being determined. Several unproven hypotheses indicate that the main factors for its development include viral superantigens (e.g., ‘s-protein’), autoimmunity secondary to molecular mimicry with anti-Ro/La detectable in patients with MIS months after recovery, post-infection immune cell activation, and reservoirs of SARS-CoV2 infection still present [22]. However, the pathophysiology that favors the development of MIS is the activation and expansion of macrophages through antibody-dependent potentiation. Antibody-dependent potentiation is observed in multiple viral infections, including respiratory syncytial virus (RSV), measles and, most importantly, dengue virus, where it is thought to underpin the pathogenesis of dengue hemorrhagic fever. The antibody-dependent potentiation mechanism occurs following interaction with pre-existing non-neutralizing antibodies and virus binding and Fc Gamma receptor interaction during viral uptake in phagocytes, which facilitates viral proliferation and the release of proinflammatory cytokines, as well as the development of immune complexes that enhance the inflammatory process. While antibody-dependent potentiation has not been seen clinically in patients with SARS-CoV2 reinfection by different strains, it may occur due to the progressive changes observed within the S protein of different SARS-CoV-2 strains. It may also explain the link between vaccination and the development of MIS in adults [23].

Thus, although less common, adult MIS adds to a growing list of hyperinflammatory syndromes, each of which can be complicated and secondary to SARS-CoV2 infection, including secondary hemophagocytic lymphohistiocytosis and capillary leak syndrome [21]. For example in a hospital, a 22-year-old patient vaccinated against SARS-CoV-2 and 3 weeks after recovering from COVID-19 was admitted with a fever of 40.5oC, myalgias, headache and vomiting. The biochemical parameters showed neutrophilia (93.2%), thrombocytopenia (3.30%) and platelets in 51 × 109/L. Unfortunately, there was no accurate diagnosis with routine examinations, so the patient’s condition worsened. Subsequently, the possible development of MIS was indicated and confirmed by increases in inflammation markers, Elevated CRP, Erythrocyte sedimentation rate, ferritin, procalcitonin, as well as elevated Troponin T, and myocarditis through ECG electrocardiogram and SARS-CoV-2 infection. With these data, the patient receives the appropriate treatment based on broad-spectrum antibiotics, corticosteroids, intravenous immunoglobulins, colchicine, and heparin [21].

3. Conclusions

The development of MIS has an interval of onset of 2–6 weeks and in some cases, there may be manifestation in the acute phase of SARS-CoV-2 infection; however, the latter is not evident since specialists agree that it may be due to the critical process or a post-infectious condition. It is essential to mention that MIS is a dangerous pathophysiological condition independent of whether the subject has has received the vaccine since factors such as genetic predisposition and comorbidities may be intrinsic in its development. Researchers agree that MIS is due to an active and prepared immune system through antibodies. The above, because the pharmacological treatment is directed at the immune system. Unfortunately, individual clinical studies are not sufficient to understand the pathophysiology of MIS, and at the same time, to provide effective treatment and follow-up to patients who have developed MIS. Another aspect to consider is the risk of relapse in MIS; therefore, randomized clinical studies are required to clarify the disease more efficiently. Finally, MIS is a complex condition that can develop after SARS-CoV-2 infection where the cellular physiology and clinical picture are still not understood.

Acknowledgments

We are grateful to the Universdad de Guanajuato, Campus Celaya-Salvatierra.

Conflict of interest

“The authors declare no conflict of interest.”