The coronavirus disease 2019 (COVID-19) pandemic has produced a world-wide collapse of social and economic infrastructure, as well as constrained our freedom of movement. This respiratory tract infection is nefarious in how it targets the most distal and highly vulnerable aspect of the human bronchopulmonary tree, specifically, the delicate yet irreplaceable alveoli that are responsible for the loading of oxygen upon red cell hemoglobin for use by all of the body's tissues.
In most symptomatic individuals, the disease is a mild immune-mediated syndrome, with limited damage to the lung tissues. About 20% of those affected experience a disease course characterized by a cataclysmic set of immune activation responses that can culminate in the diffuse and irreversible obliteration of the distal alveoli, leading to a virtual collapse of the gas-exchange apparatus.
Here, in Part I of a duology on the characterization and potential treatment for COVID-19, we define severe COVID-19 as a consequence of the ability of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to trigger what we now designate for the first time as a ‘Prolific Activation of a Network-Immune-Inflammatory Crisis’, or ‘PANIC’ Attack, in the alveolar tree. In Part II we describe an immunotherapeutic hypothesis worthy of the organization of a randomized clinical trial in order to ascertain whether a repurposed, generic, inexpensive, and widely available agent is capable of abolishing ‘PANIC’; thereby preventing or mitigating severe COVID-19, with monumental ramifications for world health, and the global pandemic that continues to threaten it.
In the severely ill COVID-19 patients, front-line healthcare workers have been largely preoccupied with providing adequate life-support, prioritizing the integrity of the respiratory and circulatory systems, and keeping blood oxygen saturation above the threshold where end organ damage ensues. In those with a rapid transition from minor symptoms to urgent admission to an ICU, the majority will require ventilator support, along with continuous observation and repeated assessments of each of the major body systems. Given the potential for any given COVID-19 patient to abruptly deteriorate, clinical management mandates a systematic sequence of intensive care measures and protocols principally aimed at avoiding a period of hypoxic ischemia. It is for this reason, at least in part, that our understanding of the neurologic manifestations of COVID-19 lags behind our understanding of the more omnipresent and existential concerns that are associated with patients so severely affected by this infection.
The ICU priorities can hinder the ability of any subspecialist to carry out their assessments, as well as limit recommendations for those investigations that require the patient to leave the ICU setting (e.g. as with the performance of imaging studies including CT and MRI). Each departure for additional testing must be cautiously weighed against the risks and benefits of such investigations. Despite these limitations, we have now gained some insights into complications of SARS-CoV-2 infection that target the CNS and peripheral nervous system (PNS)
COVID-19 neurological manifestations are thought to result from indirect and direct actions of SARS-CoV-2 on the CNS and PNS. Indirect actions of the virus are related to injury to peripheral organs, such as the lungs, kidneys, liver, and heart. For example, myocardial and lung invasion by SARS-CoV-2 could result in cardiac failure and arrhythmias, which could in turn increase the secondary risk of stroke or pulmonary embolism as a result of stasis within the chambers of the heart . Alternatively, SARS-CoV-2 could directly damage the brain and spinal cord either via hematogenous spread or via neural propagation into the CNS Other coronaviruses, such as SARS-CoV-1 and human coronavirus OC43 have been shown to enter into the nasal passages and spread to the olfactory bulb, pyriform cortex, dorsal nucleus of the rafe in the brainstem, and spinal cord.Of note, ablation within the olfactory pathway can prevent the neural spread of MHV coronavirus in animals. Cellular entry of SARS-CoV-2 occurs through the ACE-2-r. Interestingly, ACE-2-r is expressed widely in the CNS within neurons, motor cortex, hypothalamus, thalamus, and brainstem
The physical distribution of ACE-2-r in the brain could account for some of the clinical symptoms observed in patients. For example, direct neuronal injury within the brainstem cardiorespiratory centers in the medulla, could explain the peak disease cardiovascular and respiratory complications in COVID-19 patients
In addition, anosmia and ageusia in COVID-19 patients may be related to viral entry through ACE-2-r within the olfactory system or within the hypothalamus.
A recently published retrospective observational case series focused upon the neurologic manifestations of COVID-19 from Wuhan China, and included 214 consecutive hospitalized patients with laboratory-confirmed diagnosis
This analysis showed that approximately 60% of patients were designated as having mild disease, with the remainder characterized as having severe infection, defined with respect to their respiratory status. Approximately 36% of the cohort exhibited neurological manifestations, with those designated as having more severe disease being more likely to significantly harbor comorbid conditions with hypertension being most common, as well as being significantly less likely to present with the more typical respiratory symptoms (at least at presentation) of COVID-19, such as cough in the context of fever.
Patients most likely to present with neurologic symptoms tended to be significantly older, and also afflicted with severe infection, with the majority of neurologic features occurring in the CNS (e.g. stroke, potentially influenced by features of a thrombotic microangiopathy, with or without cardiac disease, impaired consciousness, headache, dizziness, anosmia, dysgeusia, etc.), versus the PNS. These same individuals were also significantly more likely to present with elevated D-dimer levels (reminiscent of a consumptive coagulopathy, such as DIC), along with multiorgan derangements, like hepatic transaminitis, renal insufficiency signified by rising blood urea nitrogen (BUN) and creatinine levels, and serum elevation of muscle creatinine kinase levels. It has been established that inflammatory disease tips the coagulation cascade to a ‘pro-coagulant state’. This has been observed in neuroinflammatory disorders, including MS and its animal counterpart, experimental autoimmune enchephalomyelitis (EAE)
Some of the patients presented with neurologic features, in the absence of typical COVID-19 symptoms, and tested negative by chest CT imaging and by COVID-19 blood testing. Days later, these individuals manifested the features of cough and sore throat, in conjunction with lymphopenia and the evolution of characteristic ‘ground-glass’ opacification lesions demonstrated on repeat chest CT. Indeed, their SARS-CoV-2 infections were later corroborated by nucleic acid testing.
Alternatively, those patients presenting with PNS features did not significantly correlate with any laboratory assessments. Dichotomizing patients categorically into severe versus non-severe COVID-19 did not significantly correspond to the presence or absence of PNS involvement.
Virology of SARS-CoV-2 infection
SARS-CoV-2 represents the third and most-widespread Coronavirus zoonosis, preceded by SARS-CoV and MERS-CoV. All three of these zoonoses are believed to have originated in bats and transitioned to humans via intermediate hosts. The Coronavirus' namesake is derived from its structural ‘crown-like’ appearance. The virus is composed of a positive sense single stranded RNA physically associated with a nucleocapsid, within a phospholipid bilayer, with the envelope decorated with externally projecting spike glycoproteins. The viral spike interacts with its receptor, ACE-2-r, on susceptible target cells to facilitate entry and viral replication.With the identification of the ACE-2-r receptor as the binding site for SARS-CoV-2 spike protein and its corresponding tropism, there was a groundswell of concern that ACE inhibitors and/or angiotensin receptor blockers would confer an increased risk upon infected patients. However, patients with COVID-19, who were treated with ACE-inhibitors or angiotensin receptor blockers, continue to derive both cardiovascular and renal protection, and in fact, the discontinuation of these agents might be harmful.
‘Irrational exuberance’ of immune-mediated inflammatory networks
Evidence is rapidly mounting to suggest that the severe lung damage in COVID-19 is the result of both the activation of diverse limbs of host immune networks, in conjunction with exaggerated activities of each of these responses to SARS-CoV-2. To more accurately account for viral induction of the coincident confluence of converging inflammatory cascades, and for differentiation of the characteristics of the immune-mediated responses in those designated to have mild versus severe COVID-19 disease, we have, for the first time to our knowledge, coined an acronym that reflects the severe magnitude and cataclysmic evolution of the severe variant of COVID-19: In essence; the PANIC Attack.
The pathophysiology of the SARS-CoV-2 triggered PANIC-attack
Role of complement in the SARS-CoV-2-triggered PANIC-attack
SARS-CoV-2 can enter cells within the lungs via the endosomal pathway, or conceivably by fusion mechanisms that might also allow for the development of syncytia. Destruction of alveolar cells expressing ACE-2-r by SARS-CoV-2 could theoretically be orchestrated by post-viral replication cell bursting, or by antigen-antibody complex triggering complement-dependent cytotoxicity (CDC) via activation of the complement pathway . Activation of the complement pathway would result in the C3a and C5a fragments acting as anaphylatoxins, through increasing the leakage of the capillary beds, and chemotaxins, serving to recruit neutrophils, monocytes, macrophages, and eosinophils into the target tissue. Upon arrival, these cells would release their immune effector mediators, including free radicals and reactive oxygen species (such as superoxide). Alternatively, distal activation of the complement pathways involving C5 convertase leads to the assembly of the C5b-C8 coordinated membrane attack complex (MAC) and the subsequent traversal of C9 into the MAC channel and across the cell membrane (i.e. the alveolar epithelium), leading to osmotic derangements culminating in cell death.
In order to ascertain the role played by the complement system in the pathobiology of COVID-19, a recently reported case series characterized the recovery of four ICU patients with severe COVID-19 associated pneumonia or ARDS, in response to eculizumab, an antibody against C5 convertase, which ultimately prevents the assembly of MAC, and thereby CDC.
Eculizumab has been FDA approved for a number of conditions where pathogenic antibody is complement fixating, and upon engagement with its antigen, there occurs the initiation of the assembly sequence involving C5b C8, that ultimately culminates in the formation of the MAC, through which C9 can then traverse and breach the integrity of the cell membrane sufficient to promote cell death. The conditions that have been shown to be effectively treated by eclulizumab include hemolytic uremic syndrome (HUS), paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis, and most recently AQP4+ neuromyelitis optica spectrum disorder (NMOSD) patients . Administration of eculizumab early in the disease course may ultimately shed light on the role of complement-dependent injury pathways on the disease burden in the distal bronchopulmonary circuit. The diverse spectrum of innate and adaptive immune activation, ignited by the SARS-CoV-2 agent, is compositionally part of our ‘PANIC’ Attack hypothesis.
We hypothesize that the early presence of both IgM and IgG directed to spike is germane to the activation of complement within the lung by the classical pathway, which is principally triggered by the recognition of antigen-antibody complexes. The latter of which must be of appropriate isotype in order to ‘fix’, and thereby activate, the classic complement cascade. The alternate and lectin activated complement cascades are also likely ignited in the lung of severely affected COVID-19 patients. The former can be activated by either C3b or via contact with surface epitopes, such as those liberated by damaged cells, while the latter pathway is antibody-independent and becomes activated when mannose binding lectin (MBL) binds to glycosylated moieties upon the surface of pathogens.
Upon convergence with the serine esterase sequence activation of the complement cascade, all three paths ultimately lead to cleavage products, such as the anaphylatoxins and chemotaxins, C3a, C4a, and C5a, which can increase vascular permeability in concert with promoting the redistribution of circulating neutrophils, eosinophils, monocytes, and macrophages into the site of the tissue localization where the complement cascades were activated. Upon their arrival, these leukocytes can elaborate a number of highly potent and injurious immune effector elements (i.e. free radicals, superoxides, etc), which together further contribute to both the process of attempted neutralization of the immune challenge, which is SARS-CoV-2, as well as potentially fomenting a considerable amount of damage to the surrounding host tissue structure (i.e. bystander damage). The anaphylatoxins C3a and C5a further intensify and perpetuate organ tissue damage in COVID-19 via escalation of IL-1, IL-6, TNFα, as well as mast cell histamine degranulation
Role of the cytokine ‘Storm’ in SARS-CoV-2 triggering of the PANIC-attack
While IL-6 is elevated in about 33% of mild COVID-19 patients, 76% of severely affected patients exhibit elevation of this pro-inflammatory cytokine. In fact, COVID-19 patients characterized as having severe disease have corresponding escalations of IL-6, TNF-α, IL-2, MCP-1, MIP-1A, IL-10, IL-7, and G-CSF, especially in ICU patients .Further, evidence of cytokine release syndrome (CRS) or ‘storm’ was confirmed by an escalation in IL-6 levels in conjunction with inadequate levels of the negative regulatory suppressor of cytokine signaling 3 (SOC 3).Perhaps the laboratory finding of greatest conspicuity in those with confirmed COVID-19 is lymphopenia, posited to potentially represent the consequence of the broadening of SARS-CoV-2 distribution and apoptosis, the terminal phenomenon of viral infection. An alternative explanation is that the lymphopenia may be due to a cortisol burst from stress. The sequestration of lymphocytes into the lungs may also be a feasible hypothesis for the circulating lymphopenia (let's recall that only 3–5% of the body's mononuclear cells are in circulation at any given time). Despite the lymphopenia, widespread lymphocyte activation is a stereotypic observation in those with the disorder, particularly associated with the severe variant
The pulmonary interstitium reveals a predominance of CD8+T cells, a response considered to be crucial for SARS-CoV-2 clearance. However, the concomitant presence of elevated levels of IL-6, and IL-8, impair the ability of T cells to prime dendritic cells against the virus, and also limit macrophage clearance of the pathogen. Similar to MERS, also characterized by augmented circulating levels of IL-6, there is a reduced production and elaboration of anti-viral cytokines, such as the type I interferons (IFN alpha and beta).
While the lung is the principal and most crucial target of attention for those with severe COVID-19, the distribution of the ACE-2-r is sufficiently wide that we are confronted with the controversy as to whether damage to the kidneys, GI tract, heart, skin, CNS, and PNS is a consequence of the reduced oxygen-carrying capacity of blood, secondary to the damage to the lung's gas exchange apparatus, or whether viral targeting of endothelium in other tissue beds can also foment the PANIC Attack, and the resultant injury mechanisms associated with such uncoordinated and poorly regulated immune activation.
The time is upon us to move urgently in order to identify therapeutic strategies which can bring to bear the necessary diversity of counterbalancing mechanisms commensurate with the wide spectrum of activated inflammatory mechanisms triggered by SARS-CoV-2, and which collectively represents the newly defined designation of PANIC Attack, extensively characterized in this paper, and which we have proposed to be directly responsible for the pathobiological underpinnings of the severe variant of COVID-19.
In Part II of our 2-part series on the COVID-19 pandemic, and the corresponding global human crisis it has produced, we advance the innovative hypothesis that the repurposed application of HDMTX-LR, represents a particularly interesting candidate therapy, worthy of investigation within the context of a randomized controlled clinical trial. This trial is needed to confirm or refute the contention that this WHO designated essential treatment can uncouple the SARS-CoV-2 triggered constellation of immune activities that compositionally represent the highly injurious PANIC Attack, which leads to obliteration of the bronchopulmonary alveolar gas-exchange apparatus, predisposing the severe COVID-19 patient to disabling morbidity, and a significant risk of mortality.
Methotrexate with leucovorin rescue is an FDA approved and generic treatment regimen, that is inexpensive, widely available, and one with an extensive experiential track record of well-identified adverse events and toxicities, while also being associated with a corresponding and longstanding effective spectrum of risk mitigtation strategies. Most importantly, HDMTX-LR represents a treatment strategy which is endowed with an impressively broad heterogeneity of anti-inflammatory properties spanning the human immune network, and which strikingly align with each of the currently identified components of the newly defined PANIC injury construct, fomented by the SARS-CoV-2 agent.
Reference & Source information: https://www.jns-journal.com/
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