NT-proBNP, N-terminal pro-brain natriuretic peptide; PT, prothrombin; PTT, partial thromboplastin time; KD, Kawasaki disease; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL, interleukin; LDH, lactate dehydrogenase; RT-PCR, reverse transcription-polymerase chain reaction. Granulomatosis with polyangiitis is a serious condition that can be fatal if left untreated, as it can lead to organ failure. Migraine headache is caused by activation of trigeminal sensory fibers by known and unknown migraine triggers. There is subsequent release of inflammatory mediators from the trigeminal nerve. This leads to distention of the large meningeal blood vessels in the skull and brain and the development of a central sensitization within the trigeminal nucleus caudalis (TNC). Genetic abnormalities may be responsible for altering the response threshold to migraine specific trigger factors in the brain of a migraineur compared to a normal individual 26. Cytokine release syndrome, also known as cytokine storm, correlates with COVID-19 severity and has been recognised as a major cause of mortality among COVID-19 patients ( 43). It is defined as a life-threatening condition involving the excessive cytokine and chemokines produced by the dysregulation of the immune response ( 43). Considering that these inflammatory mediators are interdependent and can be both protective and pathologic, distinguishing them can be challenging. In the serum of COVID-19 patients with cytokine storm, various raised cytokine levels are reported. This includes IL-1β, interleukin-6 (IL-6), tumor necrosis factor (TNF), macrophage inflammatory protein (MIP) 1α and 1β, interferon-γ, inducible protein 10 (IP-10), and VEGF ( 19, 44).

Aspirin is not usually recommended for children under 16, so do not give aspirin to your child unless advised to by their doctor.

Temporal arteritis (giant cell arteritis)

This was a retrospective, single-institution observational cohort study conducted at a quaternary care pediatric healthcare system from May 2020 to May 2021. Individuals were included if they were under 21 years old, admitted to the hospital and were diagnosed with MIS-C by 2020 Centers for Disease Control and Prevention criteria [ 21]. Cases were identified from three sources: review of all admitted patients during the study period for MIS-C diagnosis codes, an infectious disease consult running list of MIS-C patients, and critical care provider review of all patients admitted to the intensive care unit. With the benefit of insights from molecular biology that were unavailable before the 1960s, it is possible to define inflammation more broadly as a protective response, involving the activation of immune and non-immune cells, in response to an insult such as infection, toxic compounds, damaged cells, or irradiation, with the aim to restore tissue homeostasis. This raises the question as to whether inflammation is always protective [ 5]. The answer is a less-than-definitive, “it depends”. COVID-19 has been widely known to infect the human respiratory system. However, several anecdotal reports on neurological manifestations such as headache, dizziness, altered mental state, acute cerebrovascular disease, and meningoencephalitis have emerged ( 70– 73). Neurological involvements were more susceptible among those with severe infections and were the only initial presenting symptoms in some ( 70). Given the wide range of symptoms associated with COVID-19 as time unfolds, the effects of COVID-19 can be expected to occur through multiple neuro-invasive pathways. Emerging studies have described the underlying pathways via the direct (neurotropism of SARS-CoV-2) and indirect route (due to inflammation, hypoxia, thrombosis and imbalance in blood pressure). Additionally, ACE2 receptors, the principal viral entry receptor for SARS-CoV-2, are found in both neurons and non-neuronal cells (astrocytes, endothelial cells and oligodendrocytes) of the central nervous system (CNS) ( 17). Multiple CNS regions with high expression of ACE2 receptors include the amygdala, cerebral cortex and brainstem ( 74).

Inflammation in the liver protects this organ from infection and injury, but excessive inflammation may lead to extensive loss of hepatocytes, ischemia-reperfusion injury, metabolic alterations, and eventually permanent hepatic damage [ 128]. Inflammation can destroy hepatic parenchymal cells, increasing the risk of chronic liver diseases, such as non-alcoholic fatty liver disease (NAFLD) or viral hepatitis. Chronic liver diseases are a leading cause of morbidity and mortality in the US [ 129]. Respiratory support was applied to 18 patients (58%) in the anakinra group and 24 patients (77%) in the no anakinra group. The median duration of respiratory support was 5 vs. 2 days in anakinra vs. no anakinra group with no difference.The damage-associated molecular pattern (DAMP) High-Mobility Group Box 1 (HMGB1) has been found to assist SARS-CoV-2 transfer into the cytoplasm in the post-entry step and contributes to viral replication ( 20). It is also suggested that a high concentration of HMGB1 passively secreted from necrotic or activated cells further promotes inflammation ( Figure1) ( 21). In the context of COVID-19-induced neuroinflammation, HMGB1 acts on the TLR4 receptors expressed on neurons, microglial cells, and astrocytes, effectually generating cytokine release ( 21).

Panahi Y, et al. (2014). Adjuvant therapy with bioavailability‐boosted curcuminoids suppresses systemic inflammation and improves quality of life in patients with solid tumors. The severity is highly variable among individuals infected with SARS-CoV-2, ranging from asymptomatic cases up to severe respiratory disease with extrapulmonary findings ( 10– 12). Time to immunomodulatory agent was described as the duration in hours from arrival to our institution to initiation of the immunomodulatory agent including IVIG, steroids and anakinra. Rebound fever was defined as new onset fever > 24 h after IVIG was initiated. Outcomes In the propensity score matched groups, the median time from presentation to first IVIG administration was 14.1 h in the anakinra group vs. 17.6 h in the no anakinra group with no difference. The median time to steroids was 12.9 h in the anakinra group vs. 15.8 h in the no anakinra group with no difference. The median duration of steroid use was 5 days in the anakinra group vs. 4 days in the no anakinra group with no difference. The median time from presentation to first anakinra administration in the anakinra group was 26.1 h. The median duration of anakinra use was 5 days. Outcomes of matched cohort Minihane AM, et al. (2015). Low-grade inflammation, diet composition and health: Current research evidence and its translation.Neuropathic pain in contrast to nociceptive pain, is described as "burning", "electric", "tingling", and "shooting" in nature. It can be continuous or paroxysmal in presentation. Whereas nociceptive pain is caused by the stimulation of peripheral A-delta and C-polymodal pain receptors, by peripheral release of inflammatory mediators, (e.g. histamine bradykinin, substance P, etc.) neuropathic pain is produced by release of inflammatory mediators including neuropeptides and neurotransmitters secondary to injury or damage to peripheral nerves or the central nervous system Laboratory findings include lymphopenia and reduced to normal thrombocytes ( 21). In the acute phase, there is an increase in inflammatory cytokines and other molecules, such as interleukin-1β (IL-1β), IL-6, IL-8, tumor necrosis factor-α (TNF-α), IL-10, IL-17, interferon-γ (IFN-γ), IL-2 receptor agonist, C-reactive protein (CRP) and ferritin. Additionally, markers of myocardial dysfunction and injury are also increased, including N-terminal pro B-type natriuretic peptide (NT-proBNP) and troponin. In contrast to KD, in MIS-C, there is evidence of a procoagulant state establishment due to raised fibrinogen and D-dimer levels and low platelet count ( 17). and Immunity Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia