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  • Writer's pictureGraham Exelby

Long COVID Immune Dysfunction

This is the first part of a series of articles dealing with Long COVID and its management

Dr Graham Exelby and Dr Valerio Vittone May 2024


In the wake of the ongoing SARS-CoV-2 (COVID) pandemic, it is estimated there are over 60 million people globally afflicted by Long Covid. (1) It is estimated that 5-20% of people who contract COVID have ongoing cognitive dysfunction. (2)  


This document draws heavily from clinic findings, innovative radiology and extensive collaborative work at a local level, Mast cell activation research by Afrin, Weinstock and Malone (3)(4)(5), DNA assessments by Dr Valerio Vittone (6), research by Zamboni and other (7) in Multiple Sclerosis, research by Griffith University in Chronic Fatigue Syndrome and Long-Covid (8) and the comparative work on Gulf War Syndrome and Long Covid by Dr Jim Baraniuk at Georgetown University.(9)(10) and others, (11) including Hulens et al looking at the links between the Empty Sella Syndrome, Fibromyalgia and CFS.(12)  


By combining these areas of research and applying these to the patients seen at our clinic with the complex mix of POTS, Long-Covid and their co-morbidities including Ehlers-Danlos Syndrome, fibromyalgia, migraine, autoimmune disease, ADHD, Autism Spectral Disorders, and unexplained anxiety and depression, there are many areas that can be treated, in particular increased CSF pressure and increased vascular pressure in the brain.  The underlying causes of the cognitive impairment is complicated, and management usually involves both looking at the damage caused, and also at co-morbidities.    By recognizing the differences and underlying causes, individual treatment programs can be commenced that are not just based on anti-depressants and exercise.


The critical importance of the interaction between the body’s threat receptors with the main immune cells in the Central Nervous System (CNS) and the impact of abnormal levels of a neuroexcitatory neurotransmitter glutamate on these cellular structures and the dysfunction of the Natural Killer Cells and the Glymphatic System combine to provide potential areas to improve the cognitive impairment, fatigue and other symptoms.   This paper is part of a series on aspects of Long COVID with particular emphasis on cause and management of the Cognitive Impairment.


Common problems in Long COVID:


1.     Fatigue

2.     Cognitive Impairment /brain fog

3.     Shortness of breath

4.     Over 65- 60+% increased cardiovascular or cerebrovascular event in next 12 months

5.     Change in microbiome

6.     High incidence diabetes

7.     Increased incidence of autoimmune disease

8.     Neural sensitisation with autonomic dysfunction, triggering multiple problems including Postural Orthostatic Tachycardia Syndrome (POTS.)


Figure 1: Schematic Representation of a SARS-CoV-2 virion with major structural proteins

 Source: Sariol, A., Perlman, S. SARS-CoV-2 takes its Toll. Nat Immunol (78)


The Immune Response


The immune system is broadly divided into the innate immune system and the adaptive immune system.  Although the adaptive and innate immune systems are linked, they each consist of different cell types with different jobs. The adaptive immune system consists of three major cell types: B cells, CD4+ T cells, and CD8+ T cells. B cells produce antibodies. CD4+ T cells possess a range of helper and effector functionalities. CD8+ T cells kill infected cells.


The innate immune system provides the first line of defence against threats.   It does not require prior exposure to mount a response, but cannot provide long-term pathogen-specific immunological memory.   The adaptive immune system provides a specialized targeted response to threats.  It responds more slowly, taking days or weeks on first exposure, but mounts a faster, stronger response on re-exposure.  It involves T and B cells (lymphocytes) that undergo clonal expansion in response to specific antigens, and generates immunological memory.  It also helps regulate the immune system response.


Given that adaptive immune responses are important for the control and clearance of almost all viral infections that cause disease in humans, and adaptive immune responses and immune memory are central to the success of all vaccines, it is critical to understand adaptive responses to SARS-CoV-2. 


Any virus that can cause disease in humans must have at least one immune evasion mechanism. Without the ability to evade the immune system, a virus is usually harmless.  In the case of SARS-CoV-2, the virus is clearly unusually effective at evading the triggering of early innate immune responses, such as type 1 interferons (IFNs), blocking components of the IFN signalling cascade.  It also causes partial mitochondrial dysfunction, leading to increased reactive oxygen species (ROS) production.(13)(14)(15)


Secretion of chemokines and cytokines activate the T cells and B cells of the adaptive immune system. Mast-cell derived cytokines and chemokines enhance the migration of dendritic cells to the site of infection, where they ingest the pathogen. This is the start of the adaptive immune response.  In other words, TLRs act as a link between your innate and adaptive immunity.(4)


Both innate and adaptive systems are dysregulated in COVID infections.   The innate immune system provides the first line of defence against the SARS-CoV-2 virus, mobilizing neutrophils, monocytes/macrophages, dendritic cells and natural killer (NK) cells.  In COVID patients the NK cell numbers are severely reduced, the remaining NK cells robustly activated, regulating T cells of the adaptive immune system. (16), the increased adaptive/memory -like NK cells directly correlated with serum IL-6 levels. (17) 


The ”cytokine storm” that characterizes the severe COVID infections with the excessive production of pro-inflammatory cytokines IL-6 and TNFa is driven by the dysregulation of the immune system, with hyperactivation of the innate immune system and uncontrolled release of these inflammatory cytokines.(18)(19)


The cytokine storm is a result of aberrant activation of the mast cells by our immune system gate keepers, the threat receptors, or Toll-Like Receptors, releasing cytokines, which are small proteins involved in cell signalling, as well as other inflammatory products, in particular Interleukin 6 (IL-6) and Tissue Necrosis Factor alpha (or TNFa).    Inflammatory microglial activation (IL-6 and TNFa) is the most common brain pathology found in patients who died of COVID-19.  


A complex, interconnected network of cell types, signalling pathways, and cytokines is involved in cytokine storm disorders.   Interferon-γ, IL-1, IL-6, TNFa, and IL-18 are key cytokines that often have elevated levels in cytokine storm and are thought to have central immunopathologic roles. The pattern of cytokine elevations varies on the basis of such factors as the microbiome, genetic features, and underlying disorders.(18)


The immune hyperactivation in cytokine storms can occur as a result of inappropriate triggering or danger sensing, with a response initiated in the absence of a pathogen, an inappropriate or ineffective amplitude of response, involving excessive effector immune-cell activation, an overwhelming pathogen burden (e.g., in sepsis), or uncontrolled infections and prolonged immune activation.   In each of these states, there is a failure of negative feedback mechanisms that  are meant to prevent hyperinflammation and the overproduction of inflammatory cytokines and soluble mediators. The excessive cytokine  production leads to hyperinflammation and multiorgan failure.(18)


The adaptive immune system’s response to SARS-Co-V-2 involves T and antibody-producing B cells. CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to attempt to control the SARS-CoV-2 infection.  There is a 1000-fold range in the magnitude of antibody responses to the virus.(20)   CD8+ T cells are vital for viral control, but excessive T cell activation can be detrimental and markers of T cell exhaustion are associated with disease progression.(21)   In COVID the number of CD3+ T cells and CD8+ T cells are significantly lowered.(22) 


Elevated levels of pro-inflammatory cytokines are associated with many chronic diseases- cardiovascular disease, diabetes, auto-immune diseases, and even cancer.     IL-6 and TNFa release occurs in Takotsubo cardiomyopathy and is thought why the heart does not always return to normal after an “event,” and leaving persistent cardiac dysfunction.(23)


Increased IL-8 has been found in increased concentrations in the CSF in Fibromyalgia (FMS), and IL-6 and IL-8 are now thought to mediate the inflammatory response in fibromyalgia syndrome.(24) This has been confirmed in Covid investigations where the cytokines released initially in the “Cytokine storm” principally IL-6, IL-8 and TNFa.(25)


There is a common set of abnormal pathology found in our clinic in Long Covid,  with low levels of complement C3 and low CRP levels, and as such commonly passes as normal responses.  It does appear likely that this correlates with T cell exhaustion, and most likely from the TLR2/astrocyte activation.(26)(27)   The low complement C3 indicates increased consumption and activation of the complement system, and correlates with a more severe hyperinflammatory state and increased risk of coagulability.(28)(29)


DAMPs (damage-associated molecular patterns),  are endogenous danger signals that are discharged to the extracellular space in response to the cell from pathogens or mechanical trauma.   PAMPs (pathogen-associated molecular patterns) are small molecules within microbes that are recognized by TLRs and other pattern recognition receptors (PPRs), that allow the innate immune system to recognize pathogens and protect the host from infection. 


The Infection


SARS‐CoV‐2 enters the body and its spike (S) protein interacts with ACE2 receptors to infect respiratory epithelial and immune cells. During infection, rapid viral replication triggers PAMP and DAMP causing a strong immune response and immune dysregulation.(3) 


At the early stage, the virus infects the lung epithelial cells and is slowly transmitted to the other organs including the gastrointestinal tract, blood vessels, kidneys, heart, and brain. The neurological effect of the virus is mainly due to hypoxia‐driven reactive oxygen species (ROS) and generated cytokine storm. Internalization of SARS‐CoV‐2 triggers ROS production and modulation of the immunological cascade which ultimately initiates the hypercoagulable state and vascular thrombosis. (30)   Immune cells are extensively activated and secrete large amounts of inflammatory factors, causing excessive inflammation and the “cytokine storm,” which can lead to immunopathological impairment of COVID‐19, closely related to the severity of the disease. (3)


The hypercoagulability with alterations in haemostatic markers including high D-dimer levels, together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, reveals COVID-19 to be a thrombo-inflammatory disease.  Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19.(31)


Figure 2: The SARS-CoV-2 Infection

Source: Jiang Y, Zhao T, Zhou X, Xiang Y, Gutierrez-Castrellon P, Ma X. Inflammatory pathways in COVID-19: Mechanism and therapeutic interventions. (3)


Sashindranath and Nandurkar (31) described an established link between COVID-19 and neurological symptoms in up to 50% of patients, including loss of smell and taste, necrotizing encephalitis, seizures, and rarely, Guillain-Barre syndrome.   Acute cerebrovascular disease with a relatively low mean age (ranging from 45 to 67 years) is a significant complication of COVID-19.   “That the overall incidence of large vessel occlusions is 2-fold higher than in normal acute ischaemic stroke cases and they occur among patients from all age groups, even those without risk factors or comorbidities, strongly implicates COVID-19-related hypercoagulability as the underlying cause.   The endothelium has a pivotal role in cerebrovascular disease. Endothelial dysfunction occurs after stroke and leads to oxidative stress, inflammation, increased vascular tone, blood-brain barrier (BBB) damage, and further thrombovascular complications in the brain.”(31)


The pathophysiology of COVID-19 is characterized by systemic inflammation, hypoxia resulting from respiratory failure, and neuroinflammation (either due to viral neurotropism, the ability of the virus to invade and live in neural tissue, or in response to the cytokine storm), all affecting the brain. (32)

The brain and spinal cord, which make up the CNS, are not usually accessed directly by pathogenic factors in the body's circulation due to a series of endothelial cells (single layer of squamous cells that form an interface between circulating blood or lymph in the vessels, controlling the flow of substances into and out of a tissue) known as the blood -brain barrier (BBB) (formed from endothelial cells, astrocyte end-feet and pericytes.)

The BBB prevents most infections from reaching the vulnerable nervous tissue. In the case where infectious agents are directly introduced to the brain or cross the blood–brain barrier, microglial cells must react quickly to decrease inflammation and destroy the infectious agents before they damage the sensitive neural tissue, so basically are the “first responders” in infections.


Figure 3: Toll-Like Receptors 2, 3, 4


Source: Yookji, CC BY-SA 3.0 <>, via Wikimedia Commons


Threat receptors

In humans there are 10 types of body threat receptors, or Toll-Like Receptors (TLRs) that respond to a variety of PAMPs (pathogen-associated molecular patterns associated with bacteria and viruses).   TLRs are crucial components in the initiation of the innate immune system, triggering the downstream production of pro-inflammatory cytokines, interferons (IFNs) and other mediators.    TLRs recognize invading pathogens by sensing PAMP and activate the regulation of innate immunity and cytokines. TLR activation leads to the production of proinflammatory cytokines and IFN through its major downstream proteins MYS88 and TRIF.(26) 


Figure 4: Pattern Recognition Receptors in COVID‐19


Source: Mantovani S, Oliviero B, Varchetta S, Renieri A, Mondelli MU. TLRs: Innate Immune Sentries against SARS-CoV-2 Infection. Int J Mol Sci. 2023 (26)


TLRs 1,2,4,5,6,10 are plasma protein TLRs, while TLR3 and 7 are on endosomes (intracellular sorting organelles). TLR2/6 and TLR4 are located on the cell membrane


TLR2 senses the SARS-CoV-2 envelope protein (E), resulting in production of inflammatory cytokines and chemokines, contributing to the hyperinflammatory state and tissue damage seen in severe Covid.(78)(82)    The severity of the Covid infection is largely determined by the E Protein /TLR2 activation rather than the S protein.(26)(33)


TLR4 signalling is activated by the Spike protein (S).  This can lead to a pro-thrombotic and pro-inflammatory state contributing to severe complications eg myocardial infarction and acute lung injury.(34)(35) 


The endosomal TLR3 senses intracellular viral dsRNA.  Activated TLR regulates the production of proinflammatory factors through a series of signalling in the NF‐κB pathway and activates IRF3/7 to produce I IFN. (26)(36)   A DNA variant in TLR3 has also been identified as increasing susceptibility and mortality to acute COVID infections by decreasing TLR3 expression and impairing recognition of SARS-Co-V dsRNA. (26)  These results suggest perivascular inflammation may be a critical factor in Long COVID, but the role of these receptors in Long COVID associated POTS has not been established.


NFkB is a protein complex that plays a crucial role in regulating the immune response, inflammation, and cell survival. The primary function of NFkB is to control gene expression in response to various signals, such as pro-inflammatory cytokines, bacterial or viral products, stress, and oxidative damage.  NF-κB has long been considered a prototypical proinflammatory signalling pathway, largely based on the activation of NF-κB by proinflammatory cytokines such as interleukin 1 (IL-1) and tumour necrosis factor α (TNFα), and the role of NF-κB in the expression of other proinflammatory genes. 


Dysregulation of NFkB  signalling has been implicated in various health conditions, including autoimmune disorders, inflammatory diseases, cancer, and neurodegenerative diseases.(131)  Mould is a common source of continuing inflammatory activation, through its activation of the NFkB  pathway.  Research has shown that both TLR2 and TLR4 activation is involved.(37)(38)


Figure 5: Downstream Signalling Pathways of TLRs

Source: Mantovani S, Oliviero B, Varchetta S, Renieri A, Mondelli MU. TLRs: Innate Immune Sentries against SARS-CoV-2 Infection. Int J Mol Sci. 2023 (26)

Cellular Components

Damage to the brain triggers a specific type of reactive response mounted by neuroglia cells, in particular by microglia, the most prominent immune cells in the CNS and which are the first to respond to threat.(39)   Inflammatory microglial activation (IL-6 and TNFa) is the most common brain pathology found in patients who died of COVID-19: 42% are affected, and another 15% have microclots in brain tissue.(44)


This is complicated by astrocyte/ microglial “cross-talk” and neurotransmitter dysregulation.   The SARS-Co-V spike protein activates microglia leading to pro-inflammatory effects and microglial-mediated synapse elimination.  This microglial activation and neuroinflammation can disrupt the BBB.   


Covid also reduces the morphology and distribution of microglia and astrocytes in the hippocampus which has a major role in learning and memory.     Mast cells promote cross-talk between T cells and myeloid cells like microglia during neuroinflammation, and the complex interplay between the activated microglia, reactive astrocytes and mast cells is a key part of the neurological manifestations of the COVID-19 infection.(41)(42)(43)  


SARS-CoV-2 preferentially infects and replicates and propagates in astrocytes, particularly those adjacent to infected vasculature. In contrast, neurons and microglia are less likely to be directly infected. Importantly, while microglia and astrocytes are both reactivated, a direct dosage-sensitive effect of SARS-CoV-2 is only observed in reactive astrocytes.  Astrocytes are the primary targets of SARS-CoV-2 in the brain.    SARS-Co-V preferentially infects astrocytes over neurons resulting in astrocyte reactivation and neuronal death (44). 



Microglia are a type of neuroglia (glial cell in the CNS that do not produce electrical signals), that account for about 10-15% of cells found within the brain.   Microglia are key cells in overall brain maintenance and constantly monitor neuronal functions.

Microglia scan the tissue and modify their morphology and functions if and when necessary.  They are crucial for the formation, shaping, and functioning of synapses, fundamental for brain development during pre- and post-natal periods. (44)


Clough et al (46) describe: “Microglia are the resident immune cells of the Central Nervous System (CNS). Microglia have the capacity to migrate, proliferate and phagocytize.  Under physiological conditions, microglia exist in their “resting” state, however on exposure to a pathogen, microglia transition into an activated state and quickly mobilize to the site of injury to initiate an innate immune response.”  As the resident macrophage cells, they act as the first and main form of active immune defence in the CNS.


Astrocytes are the most abundant glial cells in the CNS.   They are pivotal in maintaining CNS homeostasis, including neurotransmitter regulation, particularly glutamate.   It is believed that astrocyte reactivity and subsequent glutamate dysregulation contributes to neurological symptoms eg cognitive impairment, fatigue and mood disorders in COVID, very similar to the neurodivergence that occurred in the Gulf War Syndrome. If the brain is not directly damaged, resolution of systemic pathology usually results in restoration of the physiological homeostatic status of neuroglial cells. (39)


Blood flow in the brain is regulated by neurons and astrocytes.   Attwell et al (47) describe “It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles.”   Astrocytes can promote the induction and progression of inflammatory states, which are significantly associated with the disease status or severity.(48)


Activation of TLR2, the other immune system “first responder” appears to affect the astrocytes.   The astrocytes form the paravascular spaces thus dysfunction in the astrocytes can affect the glymphatic system function (reducing toxin clearance from the brain.)  It is proposed that cerebrospinal fluid enters the brain via paravascular spaces along arteries, mixes with interstitial fluid, and leaves via paravascular spaces along veins.(49)

Astrocyte/glutamate dysfunction has been found in the Gulf War Syndrome, where service personnel were plagued by a variety of medical problems  including “neurodivergence,” caused by exposure to herbicides and other toxic chemicals.  This glutamate association has also been seen in Fibromyalgia, ADHD, Autism Spectrum, migraine, visual snow and other neurological dysfunction. (106)(107)(108)  

The mechanism proposed by Guedj and associates in Long Covid,(53) links these to astroglial/glutamate dysfunction.(50)(51(52)  Astrocyte dysfunction, by affecting glymphatic function, is thought to play its role in fatigue and Intracranial Hypertension as “toxin” clearance in the brain via the glymphatic system is impaired.

Figure 6: Mast Cell, Microglia and Astrocyte Cross-Talk

Source: Carthy, Elliott & Ellender, Tommas. (2021). Histamine, Neuroinflammation and Neurodevelopment: A Review. Frontiers in Neuroscience. 15. 10.3389/fnins.2021.680214.(45)

Mast Cells

The mast cell is a potent immune cell known for its functions in host defence responses and diseases, such as asthma and allergies.  “Mast cells play a key role in homeostatic mechanisms and surveillance, recognizing and responding to different pathogens, and tissue injury.   An abundance of mast cells reside in connective tissue that borders with the external world (the skin as well as gastrointestinal, respiratory, and urogenital tracts.) (71)


Mast cells are located perivascularly close to nerve endings and ANS sites eg carotid bodies and the adrenals, allowing them to potentially regulate and be affected by autonomic function.  They can be triggered not only by allergens but also by triggers from the ANS, releasing neuro-sensitizing, pro-inflammatory and vasoactive mediators.


Mast cells regulate the functions of immune cells such as dendritic cells, monocytes/macrophages, granulocytes, T cells, B cells and Natural Killer (NK) cells.   They recruit immune cells to inflamed tissue by secreting chemokines and other mediators which locally increase vascular permeability

Mast cells are activated by cytokines from TLR4.  They contribute to coronavirus-induced inflammation through mechanisms like degranulation and histamine release.  Mast cell mediators can disrupt connective tissue integrity.


Histamine and tryptase can degrade the extracellular matrix and disrupt the integrity of connective tissue.   Proteases eg  chymase can inhibit collagen synthesis by smooth muscle cells, weakening the connective tissue structure, and mast cell-derived mediators like TNFa can induce apoptosis of smooth muscle cells, further compromising the connective tissue.  Prostaglandins and leukotrienes contribute to inflammation and pain.(58)(59)   Clinic observations have demonstrated collagen changes occurring after COVID infections.


Mast cells are increasingly seen as important in the communication between peripheral nerve endings and cells of the immune system. Alim et al (55)  confirmed the binding of glutamate to glutamate receptors on the mast cell surface.    Further, glutamate had extensive effects on gene expression in the mast cells, including the upregulation of pro-inflammatory components such as IL-6 and CCL2.(55)

Dong et al (56) demonstrated that brain inflammation plays a critical role in the pathophysiology of brain diseases.  They demonstrated that in the brain, activation of mast cells triggers activation of microglia, increased cytokine and TLR4 expression, whereas stabilisation of mast cells with disodium cromoglycate (Cromolyn) inhibited the CNS inflammation that would otherwise result from activation of microglia.(56)


Microglia, the resident immune cells in the brain, play an important role in brain inflammation, while brain mast cells, rather than microglia, are the "first responders" to the injury to the brain. The complex nature of the immune response and mast cell activation in now an integral part of Long Covid pathogenesis.(56)


Theoharidis et al (57) also felt that thalamic mast cells contribute to inflammation and pain in fibromyalgia by releasing neuro-sensitizing molecules that include histamine, IL-1β, IL-6 and TNF, as well as calcitonin-gene related peptide (CGRP), HK-1 and SP.  The importance of this mast cell activation has been confirmed in COVID research.


Afrin (3) describes “Fatigue and malaise are the most common complaints in MCAS.    Most patients remain functional, but some are severely impaired.   Low-grade temperature dysregulation is not uncommon, as are lymph node swelling, weight loss, unexplained weight gain, loss of appetite, fluctuating oedema, but it is the gain in adipose tissue that accounts for weight increase in most MCAS.   These patients may have bariatric surgery sometimes with complications of poor wound healing, and while there is initial weight loss, the other symptoms usually remain, and the weight gain slowly starts to return.  Mast cells are programmed to site themselves at environmental interfaces- lungs, gut, skin, bladder, nose and sinuses etc, so there can be a wide range of pathology in aberrant mast cell activation.”  


“Mast cell activation syndrome is known to permanently escalate its baseline level of dysfunction of the affected mast cells shortly after a major stressor, likely due to complex interactions between epigenetic abnormalities and the stressor’s induced cytokine storm- of additional mutations by the mutated stem cells from which the mutated /dysfunctional mast cells are derived.”(3)


In a similar fashion, Afrin et al (3) describe post-infectious multisystem inflammatory syndromes, eg from Ebstein-Barr virus and tick-borne infections, are suspected to be rooted in initiation of mutations of normal stem cells leading to aberrant controller genes.


Malone et al (4) describe “Mast cell histamine has been implicated in the pathophysiology of COVID-19 as a regulator of proinflammatory, fibrotic, and thrombogenic processes. Histamine is an endogenous biogenic amine that functions as a neurotransmitter and an immunoregulatory factor. In the immune system, histamine is mainly stored in cytoplasmic granules of mast cells and basophils and is released upon triggering along with other mediators such as serotonin, proteases (e.g., tryptase and chymase), heparin, a variety of cytokines, and angiogenic factors.  Histamine release can be activated by numerous innate signals or exogenous triggers including allergens, toxins, and viruses.”(4)

Table 1: Organ and system involvement in mast cell activation syndrome. Conditions highlighted in red are also seen in Covid-19 acute infection and/or post-infectious syndrome.

Organ/system                           Symptom/finding

  • Constitutional                           Fatigue, fevers, chills, weight loss, weight gain

  • Ears, nose and throat             Conjunctivitis, rhinitis, sinusitis, dysosmia/anosmia, tinnitus, hearing loss, dysgeusia/ageusia, sore throat

  • Neurologic                                Headaches, migraines, brain fog, anxiety, depression, insomnia, seizures

  • Cardiovascular                         Chest pain, palpitations, hypotension

  • Pulmonary                                Cough, dyspnoea, wheezing

  • Urogenital                                 Frequency, urgency, dysuria, pelvic pain

  • Oesophageal                           Heartburn, dysphagia, globus, chest pain

  • Stomach                                   Dyspepsia, nausea, vomiting

  • Small intestine/colon               Bloating, food intolerance, abdominal pain, diarrhoea, constipation

  • Hepatic                                      Elevated transaminases, hepatomegaly

  • Salivary Glands                       Swelling

  • Lymphatics                               Lymphadenopathy

  • Dermatologic                            Flushing, pruritis, urticaria, haemangiomas, nodules, rashes, alopecia

  • Musculoskeletal                       Myalgias, arthralgias, oedema


Source: Afrin, Lawrence; Weinstock, Leonard; Molderings, Gerhard. Covid-19 Hyperinflammation and post-Covid 19 may be rooted in Mast Cell Activation Syndrome. 2020: International Journal of Infectious Diseases 100, 327-332.(3)

The prevalence of Mast Cell Activation Syndrome (MCAS) is similar to that of severe cases in the COVID infected population, and much of the COVID hyperinflammation is remarkably similar to mast cell-driven inflammatory processes.  The wide range of symptoms seen in post-COVID conditions are those seen in POTS and its auto-immune co-morbidities, as described by Afrin et al(3)     Malone et al (4) describe histamine exerting its biological actions through four types of histamine  receptors (i.e., H1 receptor, H2 receptor, H3 receptor, and H4 receptor).   It also activates  acute immune-mediated reactions and enhances vascular smooth muscle contraction and the migration of other immune cells, antibodies, and mediators to the site of insult.  The release of histamine by perivascular mast cells may also affect adjacent lymphatic vessel    function inducing immune cell trafficking through its lumen, which potentially contribute to acute inflammatory stimulus. 

Malone et al (4)  propose a paradigm where COVID-19 infection- induced mast cell activation could account for some of the core pathologic cascade and much of the unusual symptomatology associated with COVID-19 pharmacologic findings suggesting potential benefits of histamine H2 receptor blockade using famotidine.  This model is also supported by the significant overlap in the clinical signs and symptoms of the initial phase of COVID-19 disease and those of mast cell activation syndrome (MCAS) as well similarities to Dengue haemorrhagic fever and shock syndrome (including T cell depletion) during the later phase of COVID-19. 


Drugs with activity against mast cells or their mediators have been shown to be helpful in management of COVID patients.   Afrin’s group (3) describes how none of his treated MCAS patients with COVID-19 suffered a severe course of the infection and he conjectures this is because their dysfunctional mast cells were at least under partial control during the acute infections.   


Mast cell activation plays a central role in pathophysiology of EDS, Breast implant illness, collagen degeneration and can play an important role in POTS, where the association between Mast Cell Activation Disorder and POTS have been documented. 


Natural Killer Cells

Manek and Singh (60) described: “A balanced immune regulation is crucial for recognizing an invading pathogen, its killing, and elimination. Toll‐like receptors (TLRs) are the key regulators of the innate immune system.”

The adaptive immune system includes the T cells and B cells. Unlike the cells of the innate immune system, T cells and B cells can identify specific features of pathogens – or cancer. DNA provides the instructions for a cell’s growth, survival and reproduction. When there’s a change in the DNA, it can cause a cell to divide more quickly and, in some cases, lead to cancer. It also slightly changes the protein the cell produces, but T cells and B cells can recognize this subtle difference and identify the cell as harmful.(61)

T cells protect us from infection. In our daily lives, we’re constantly exposed to pathogens, such as bacteria, viruses and fungi. Without T lymphocytes, also called T cells, every exposure could be life-threatening. Cytotoxic T cells can wipe out infected or cancerous cells. They also direct the immune response by helping B lymphocytes to eliminate invading pathogens.(61)

B cells create antibodies. B lymphocytes, also called B cells, create proteins called antibodies that bind to pathogens or to foreign substances, such as toxins, to neutralize them. For example, an antibody can bind to a virus, which prevents it from entering a normal cell and causing infection. B cells can also recruit other cells to help destroy an infected cell. (61)


Natural Killer Cells (NK cells) are a type of cytotoxic lymphocyte critical to the innate immune system, representing 5-20% of all circulating lymphocytes in humans.   The role of NK cells is analogous to that of cytotoxic T cells of the adaptive immune response. NK cells provide rapid responses to  virus-infected cells, stressed cells, tumour cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors.(63) NK cells can distinguish malignant from healthy cells.(62)


Under normal conditions, the natural killer (NK) cells of innate immunity and T‐cell of adaptive immune response have the tendency to cause the apoptosis of antigen presenting cells (APC) and prevent unnecessary activation and a balanced immune regulation is maintained, but any alterations in the lymphocyte catalytic activity due to the acquired infection in SARS‐COV‐2 infected patients dysregulate the immune balance by inactivating the NK cells as well cytotoxic T‐cells to kill the APC, leading to the dysregulated interactions of innate and adaptive immunity with consequent “cytokine storm.”(60)


Complement, Covid Severity and prognostic tests


Recent studies have found low complement C3 and CD8+ lymphopenia may warn of a poorer prognosis.  The complement family is an important integral component of the innate immune response to viruses, not only protecting the body from infectious agents such as viruses and bacteria, but also playing a key role in promoting inflammatory processes triggering the inflammatory cytokine storm.(64)


The complement system consists of a number of small proteins that are synthesized by the liver, and circulate in the blood as inactive precursors.   When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages.(65)


Complement C3 is a protein that has a central role in activation of the “complement system” is a part of the immune system enhances (complements) the ability of antibodies and phagocytic cells to clear microbes  and damaged cells from an organism, promote inflammation and attack the pathogen's cell membrane. (65)


By and large, C3 is often decreased through consumption during infections whereas a combined reduction in C3 and C4 is observed in immune complex disease. Zinellu et al (66) showed that lower serum concentrations of C3 and C4, indicating excessive complement activation and product consumption, are significantly associated with the presence of severe disease and increased mortality in patients with COVID-19.


Complement activation occurs in COVID-19 and serves different roles depending on the time course of the infection.  Early on, complement is required to assist antiviral responses, such as clearing of complement-coated virions. Later, in the subset of patients with severe COVID-19 disease (too much virus or tissue damage), complement drives several of the observed pathogenic features.(70)


The counts of all T lymphocyte subsets were markedly lower in non-survivors than in survivors, especially CD8+ T cells. (67) Older age and higher levels of C‑reactive protein,interleukin‑6, and lactate are thought to predict COVID‑19 progression.  T lymphocyte, especially  CD8+ cell‑mediated immunity is critical in recovery of COVID‑19. (68)


Low level of complement C3 may be an alert to the older COVID-19 patients as requiring additional management and a higher risk.  Critically low levels of complement C3 indicate an inability for the immune response to initiate, causing an immediate failure of anti-viral immune protection, whereas elevated levels of complement C3 may lead to excessive production of cytokine via diverse signalling pathways, causing a cytokine storm.  Young patients have a more active immune function, which is why elevated levels of serum complement C3 may be a potential indicator of the severity of COVID-19 patients.(69)




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