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Clinical Infection & Immunity

Letter to the Editor

Volume 6, Number 1, March 2021, pages 24-27

An Infection Model for COVID-19

We wish to propose an infection model to address some of the unique and unusual features observed in coronavirus disease 2019 (COVID-19), e.g., why were severe patients mounting more intense immune response compared to the mild cases, and why did severe patients demonstrate higher and more protracted viral shedding when their immune responses were more intense. In this exposition, we will first construct a pathogenic model for COVID-19, and followed with a discussion on how it may influence critical aspects of COVID-19 management. By extrapolating from this model, we will highlight important and potential therapeutic strategies. This proposed model is intended to provide a generalized framework, but it requires validation from further clinical studies.

Inflammatory reaction in COVID-19 had been studied extensively and a common theme has emerged to support a direct correlation between hyperinflammatory response and severe disease outcome, as evidenced by higher expression of proinflammatory cytokines and COVID-19 specific immunoglobulins in severe as compared to the mild cases [1]. This delta difference in the quantitative response is indicative of the degree of hyperinflammation in severe disease. As a general guide, antibody seroconversion is detectable from day 6 and peaks by day 14 [1]. This temporal sequence matches the onset of acute respiratory distress in COVID-19, which was reported to occur between day 6 to day 12 with median of day 8 from initiation of symptom [2]. Thus the development of severe disease is likely to ensue from the hyperinflammatory immune response. Since it is superfluous rather than absent/impaired immunological response associated with onset of respiratory distress, this observation may indicate a defective regulation of immunological reaction involving insufficient or dysfunctional regulatory T (Treg) upstream as a key determinant. This is supported by a study which demonstrated impairment of FOXP3-mediated negative feedback in CD4⁺T cells in severe COVID-19 [3]. The speculation of an impaired Treg function also corroborates with another series of evidence in COVID-19, i.e., the inverse association of vitamin D level with disease severity since vitamin D inadequacy can result in insufficient/dysfunctional Treg [4]. Beside its influence on Treg, vitamin D was also shown to exert direct effect on B cells suppressing the differentiation of plasma cells and class-switched memory B cells, thus modulating immunoglobulin production. Though a few reports had demonstrated lymphocytopenia contrary to hyperinflammatory hypothesis, this may not be reflective of the situation in lung because T cell recruitment to site of infection may contribute to reduced numbers in blood compartment.

The next critical question is why does a heightened immunoglobulin response which is expected to clear the viral load more efficiently actually ended up as a severe disease. We speculate that it is related to the higher affinity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) for angiotensin-converting enzyme 2 (ACE2) expressed on endothelial cells [5]. This increases infectivity within the vascular compartment, and when coupled with enhanced immunoglobulin reaction can incite significant macrophage/monocyte activation to trigger coagulation pathways, generating severe microvascular thrombosis in the lungs as demonstrated in COVID-19 autopsies. We postulate that these thrombosed vascular channels can impair subsequent immune access to the site of infection and retard further viral clearance, thus accounting for the paradoxical higher viral shedding in severe cases even in the face of stronger immune reaction [6]. Thus far, involvement of cytotoxic T lymphocyte has not been conclusively proven but is likely to contribute as evidenced by the moderate lymphocytic infiltrates in lung biopsy and increased inflammatory profile including both Th1/Th2 cytokines.

Beyond this regional extension, viruses not contained within the local environment may spread distally as supported by reports of viral involvement in gut, kidney, brain and lower limb digits. The exact mechanism of spread has not been ascertained conclusively, but it is possibly through hematogenous and/or direct oral route. For cases involving the gut, COVID-19 cases with microbial dysbiosis are associated with worst outcome; and this supports the importance of maintaining normal gastrointestinal microbiome to improve outcome [7].

Based on the COVID-19 model described above, critical treatment elements will include antivirals and reversal of dysimmune-coagulopathy. The efficacy of antivirals will depend on the mode of action, time and route of administration and degree of baseline vasculopathy. Direct antiviral therapy, e.g., ivermectin will exert greatest benefit if starting within 3 - 5 days from onset of symptoms to eliminate viral load rapidly, whereas initiating treatment later may not result in complete or rapid resolution, depending on the extent of baseline and new vascular compromise in regional and distal sites. Indirect antiviral therapy which functions by augmenting immune response may be harmful if given after onset of severe infection, because it may enhance hyperinflammation and culminate in worst vasculo-coagulopathy. However if indirect antivirals are administered before onset of severe infection, e.g., induction or infusion of protective immunoglobulin, can benefit by potentiating swift neutralization of viral agents upfront before commencement of vascular damages and coagulopathy. The route of administration is another important consideration especially when the vascular access is compromised by excessive microvascular thrombosis. Therefore without adequate vascular access in severe COVID-19, antiviral drug may need to be nebulized and administered directly into airway space to achieve best therapeutic effect.

Concurrent immunomodulation to restore Treg suppression, enhancement of vascular integrity and maintenance of normal gut microbiome can contribute to minimize hyperimmune damages. Vitamin D is a promising candidate to restore Treg suppression especially since vitamin D insufficiency is prevalent in severe COVID-19 patients [8]. By adding magnesium as a critical factor in the synthesis and activation of vitamin D may obviate the need for high-dose vitamin D [9]. Besides, magnesium is important for maintaining endothelial function and vascular integrity, improves control of hypertension, exert anti-thrombotic effect and reduces airway hyper-reactivity, together can provide additional benefit in mitigating vasculo-coagulopathy [10]. Vitamin B12 plays an important role in facilitating respiration in anaerobic environment in the gut, rendering it essential to support a healthy gut microbiome, which in turn plays important role in proper function of both innate and adaptive immune systems [11]. This could be pivotal in modulating excessive immune reaction especially COVID-19 patients with microbiota dysbiosis who were associated with severe disease.

Therefore administering a combination of vitamin D, magnesium and vitamin B12 (DMB) may synergistically improve COVID-19 outcome, which is supported by a small clinical study which demonstrated potential reduction of severe outcome by supplementing DMB in COVID-19 patients [12]. However, efficacy of DMB may depend on time of administration and degree of baseline immune-vasculopathy as well. Since DMB is not immediate acting, other agents may exert rapid immunocoagulo-modulation, e.g., corticosteroids and anticoagulants may be required when patients are presented upfront with severe disease. If serum level is intended to guide replacement, users need to be aware that magnesium deficiency can be present despite normal serum magnesium level [13]. Although DMB may benefit after onset of infection, the greatest value is probably to start DMB as prophylaxis to normalize Treg function/vascular integrity/gut microbiome even before onset of infection. Finally during recovery after acute COVID-19 infection, it may still be important to maintain DMB supplement in order to sustain a normalized immune-vasculocoagulation function. This may play a role in improving post-COVID syndrome as well as preventing excessive immune reaction even for other non-COVID respiratory infection in the future. Beside DMB, other supplements, e.g., other vitamin B complex, zinc, and vitamin C may also play important immunomodulatory role and should be tested in COVID-19 patients. As all agents in DMB are relatively common and innocuous, we believe they can be rendered readily available to patients especially those residing in economically challenged countries, since many of them may not have access to the more targeted but expensive therapeutic alternatives.

Sufficient DMB may be important not only in COVID-19 patients but similar deficiency had also been reported in conventional diabetic patients with improved disease control by administrating these supplements [14]. Thus DMB deficiency may indeed be the critical factors responsible for severe outcome commonly observed in patients with metabolic associated diseases. Besides, COVID-19 patients who develop new onset of diabetes [15] may represent those predisposed with DMB insufficiency, and diabetes was triggered by viral involvement in pancreas. If DMB deficiency is indeed proven in future clinical trials to constitute the primary determinants of severity in metabolic associated diseases, the need to restore adequate DMB levels may have wider medical implication beyond COVID-19 (Fig. 1).

Click for large image

Figure 1. Proposed model for COVID-19 with therapeutic strategies. COVID-19: coronavirus disease 2019.

The pathogenesis for severe COVID-19 is a collective result of: 1) dysregulated T and B activation with excessive immune response; 2) higher propensity of SARS-CoV-2 entering vascular compartment, which will trigger extensive microvascular thrombosis; 3) thrombosis that will limit subsequent vascular access, impairing further viral clearance; and 4) virus that can spread to distal organs affecting multiple sites. Effective therapy needs to manage immune dysregulation, vascular-coagulopathy and multi-organ dysfunction. The efficacy of therapeutic agents will depend on the mode of action, time and route of administration and degree of baseline immunovasculopathy. A combination of DMB may exert synergistic benefit in COVID-19 patients. DMB insufficiency is important in diabetes mellitus, and may play a role in pathogenesis of COVID-19 associated diabetes.

Acknowledgments

The authors are grateful to Dr. Permeen Yusoff (Office of Research, SGH) for proofreading this manuscript, as well as the continued support from SingHealth and Singapore General Hospital (SGH).

Financial Disclosure

All authors have no financial disclosures to report.

Conflict of Interest

None to declare.

Informed Consent

Not applicable.

Author Contributions

LPH has conceptualized and written this manuscript with important input from CWT, JWMC, CN, and HJN. All authors have read and agreed with the manuscript.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

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Clinical Infection and Immunity is published by Elmer Press Inc.