Question

Compare between hypersensitivity reactions and the severe symptoms that some people develop due to cytokines storm phenomena? (according to COVID-19 ) ***I don't want it to be handwritten)

Answer 1

Severe acute respiratory syndrome coronavirus-2, the causative agent of coronavirus disease 2019 (COVID-19), was declared a pandemic by the World Health Organization on 11^th March 2020 and is a major global health concern. Tyrell and Bynoe in 1966 were first described and cultivated coronaviruses as enveloped, positive single-stranded large RNA viruses that infect humans and animals. The median incubation period after infection is three days ranged from 0 to 24 days. The clinical manifestation of the disease consisting of fever, dry cough, nasal congestion, fatigue, headache and the disease progress to dyspnoea and pneumonia. COVID-19 infects lung alveolar epithelial cells using receptor-mediated endocytosis through coronavirus S (spike) protein contains a ligand binding domain with the angiotensin-converting enzyme II (ACE2), After virus entery; the first line of defence mechanism (Innate) is recognition of invaded virus by pathogen associated molecular patterns (PAMPs) via endosomal RNA receptors, TLR3, TLR7 and the cytosolic RNA sensor, RIG-I/MDA5. This recognition leads to activation of the downstream signaling cascade NF-κB and IRF3 that induce expression of type I IFN and other pro-inflammatory cytokines that activates the JAK-STAT pathway that initiate the transcription of IFN type 1. There is also increased in number of neutrophils and decrease in number of lymphocytes (lymphopenia) which is the second line of defense mechanism (adaptive) and elevated of inflammatory markers like C-reactive protein and proinflammatory cytokines like IL-2, IL-7, IL-10, G-CSF, IP-10, MCP-1, MIP-1A, and TNFα which is correlate with disease severity and death . The virus then directly infects macrophages and T cells . The macrophages will present viral antigenic peptide to T cells that differentiate into follicular helper cells (T_FH cells), activated T cells CD4, CD8 + T cells and antibody secreting cells (ASC). This will recruitment of different immune cell populations ASCs, TFH cells and activated CD4 + and CD8 + T cells with IgM and IgG SARS-CoV-2-binding antibodies in the patient’s blood. The COVID-19 viral antigens lead to stimulate antibodies formation of IgM in acute phase and IgG type in chronic phase which is facilitate viral entry and fusion with infected cell through uptake of the virus-IgG complex via the Fc family of receptors and later viral fusion with antigen presenting cells like macrophages, B cells, monocytes via FcR family, and vascular endothelium through the neonatal Fc receptor (nFcR) instead of antibodies induced viral agglutination and this is known as antibody dependent enhancement (ADE). This Ag-Ab ( IgG1 and IgG3) immune complex that deposit in the lung will also end in complement activation by classical pathway of the complement (membrane attack complex MAC) end in formation C3a, C5a and C5b67 that leads to vasoactive amines release from mast cell and basophile and platelets aggregation leads to microthrombus formation which block coronary blood vessels of the heart and also leads to neutophiles infiltration and aggregation at site of infection in alveoli leading to sever tissue damage which is the main cell in type III hypersensitivity reaction and the patient showed increased in neutrophils number which is the same immune mechanism in rheumatoid arthritis. Thus function of complement activation instead of viral clearance and antigen presentation, phagocytosis now act as other route for viral infection. In addition to that; the immune complex Anti-S protein:CoV immune complexes leads to increased cytokine release like MCP-1 and IL-8 in lung macrophages which is known as cytokine storm syndrome.

Scientists reported the clinical features and cytokine profile of critically ill patients with COVID-19 in Wuhan, China, and suggested that a cytokine storm (i.e. higher concentrations of granulocyte-colony stimulating factor, interferon gamma-induced protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1α and tumour necrosis factor α) could be associated with the severity of disease. They also reported that increased expression of interleukin (IL)-2R and IL-6 in serum appears to predict the severity and prognosis of patients with COVID-19. Additionally, pathological examination of a biopsy sample from a patient who died from COVID-19 revealed interstitial mononuclear inflammatory infiltrates in both lungs, dominated by lymphocytes. Furthermore, peripheral blood flow cytometric analysis showed that overactivation of T cells accounted, in part, for the severe immune injury in this patient. Thus, cytokine storms should not be neglected in the treatment of COVID-19. To date, the therapeutic options for severe COVID-19 remain limited. Several antiviral drugs, such as lopinavir, ritonavir, have shown no benefits compared with standard care. A new treatment strategy, in addition to antiviral therapy alone, is likely to be required to have a significant impact on clinical outcome. Immunomodulatory therapy to down-regulate the cytokine storm may provide insights into the treatment of COVID-19. Combined use of an immunomodulatory agent – to reduce the cytokine storm – with an antiviral agent may give physicians more time to provide supportive treatment for patients with COVID-19.

Corticosteroids are among the most commonly used drugs for immunomodulatory therapy of infectious diseases, but the use of corticosteroids in the treatment of COVID-19 can cause host immune suppression and delay viral clearance. According to treatment experiences in China, cautious use of corticosteroids is only recommended in certain critically ill patients (e.g. those with hypoxaemia) at low-to-moderate doses for a short duration.

Recently, chloroquine and its derivative hydroxychloroquine have been used in the treatment of COVID-19. Both chloroquine and hydroxychloroquine are weak bases and are able to accumulate in acidic organelles (e.g. lysosomes); as such, they can increase endosomal/lysosomal pH and inhibit viral replication. Chloroquine and hydroxychloroquine can inhibit major histocompatibility complex class II expression, antigen presentation and immune activation (reducing CD154 expression by T cells) via Toll-like receptor signalling and cGAS stimulation of interferon genes. Thus, chloroquine and hydroxychloroquine can reduce the production of various pro-inflammatory cytokines, such as IL-1, IL-6, interferon-α and tumour necrosis factor, which are involved in the cytokine storm. These immunomodulatory effects synergize their antiviral effects in the treatment of COVID-19. Immunomodulatory agents that directly target the key cytokines involved in COVID-19 may also help to alleviate hyperinflammation symptoms in severe cases.