Part I. SARS-CoV-2 triggered ‘PANIC’1 attack in severe COVID-19
Elliot M. Frohman, Nicole R. Villemarette-Pittman, […], and Teresa C. Frohman
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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.
Keywords: Cytokine, Methotrexate, Complement, Innate immunity, Adaptive immunity, Alveoli, Gas exchange, SARS-CoV-2, COVID-19, Spike protein, ACE-2-r
Rarely before has civilization been confronted with such a formidable enemy, one that is wholly invisible, often resulting in no identifiable symptoms, and yet, it is highly transmissible and the cause of a rapidly disseminated viral pandemic. The monumental penetrance of this microbe has culminated in the virtual collapse of nearly every endeavor which entails the close proximity of one human being to another. The majority (~80%) of those infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experience a mild to moderate flu-like respiratory tract illness, Coronavirus Disease 2019 (COVID-19). The minority of those infected (~20%) experience a severe disease course that can result in death . Without equivocation, SARS-CoV-2 is endowed with two fundamental characteristics, which when combined together, can foment incontrovertibly one of the most ominous semiologic courses of illness recognized in modern medicine.
Firstly, SARS-CoV-2 targets its entry receptor, through which it mediates its viral tropism. Specifically, the SARS-CoV-2 surface glycoprotein, ‘spike’, binds to the angiotensin converting enzyme (ACE-2-r) receptor , which is broadly distributed throughout the body. This Coronavirus binds with particular predilection for the extreme terminus of our bronchopulmonary anatomy, especially the alveolar gas-exchange apparatus, which is responsible for the continuous loading and subsequent delivery of oxygen to all of the tissues of the body.
Secondly, while the majority of COVID-19 patients will mount an appropriate, coordinated, and highly regulated host-immune-response to the etiologic agent, approximately 20% of infected individuals shall instead be subjected to the consequences of the ability of SARS-CoV-2 to trigger a ‘prolific activation of a network-immune-inflammatory crisis’, or ‘PANIC’ Attack. The latter host response involves the widely and indiscriminantly activated limbs of the entire immune response network, which results in a confluence of convergent immune effector elements (Table 1 ). Targeted sites include the most delicate and vulnerable of our life-sustaining circuitries, resulting in the cataclysmic obliteration of lung alveoli by exceeding a damage threshold for these indespensible and slow to repair gas-exchange structures – often exceeding the repair and replacement mechanism leading to ultimate end stage organ damage and potentially death.
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Prolific Activation of a Network-Immune Inflammatory Crisis [PANIC]:A New Pathophysiologic Signature for Severe COVID-19.
Overwhelming the limiting threshold for damage to our 600 million alveoli has been associated with the abrupt collapse of circulatory oxygen saturation and delivery, which becomes refractory to any intervention, thereby presaging multiorgan hypoxic-ischemia and death. The designation of severe COVID-19 can be characterized by a number of risk factors and clinical manifestations that implicate the nervous system as either a target tissue of the disorder’s pathophysiologic underpinnings, or as playing a fundamental role in the compromise in the fidelity of centrally integrated regulatory mechanisms which both ‘sense’ and respond to alterations in respiratory metrics. To illustrate one such pathway, trace the partial pressures of oxygen and carbon dioxide as codified by the sensing apparatus in the carotid bodies, and transmitted via the nerves of Hering (small branch of the glossopharyngeal nerve), to the solitary tract and nucleus localized to the caudal medullary tegementum. The integrity of the complex connectivity of this circuitry must be maintained in order to achieve its goal of regulating all functions of the respiratory system to maintain oxygen saturation and delivery to ensure continuous organ tissue viability.
A principal goal herein is to confirm both face and construct validity for the principle of this new definition for a poorly coordinated and dysregulated sequence of coincidentally activated limbs of the immune network (i.e. PANIC), and the consequences of such upon the primary target tissue for an infection as virulent and strategically ominous as SARS-CoV-2. Further, given the prolific immune activation associated with microbial-induced ‘PANIC’, in Part II of this publication, we advance the hypothesis that effective therapy should thereby provide a pleiotropic strategy commensurate with the range of the immune system’s diversity of activation by SARS-CoV-2.
SARS-CoV-2 triggers PANIC which the authors find reminiscent of phenomenonlogy which we have previously identified (and published in the Journal of the Neuological Sciences) as ‘monumentally severe central nervous system (CNS) inflammatory syndromes’ that were associated with multiple sclerosis (MS), neuromyelitis optica (NMO), and Sjogren’s syndrome myelitis; all of which were refractory to conventional, even intensive, immunotherapy. The successful rescue intervention reported utilized the application of high-dose methotrexate with leucovorin rescue (HDMTX-LR), an intensive and highly pleiotropic anti-inflammatory strategy . Since then, we have treated a broadening diversity of other causes that we believe to be variants of ‘PANIC’, including other post-infectious (e.g. post-adenovirus) [Fig. 1 ] and post-vaccinal (e.g. post-dTap) encephalomyelitides [Fig. 2 ]. Though classically defined as nuances of acute disseminated encephalomyelitis (ADEM), they were, however, recalcitrant to conventional immunotherapy, but were stereotypically abolished utilizing our HDMTX-LR treatment strategy.