Perspective Adjunctive Therapies for COVID-19: Beyond Antiviral Therapy

Ho, P. P.; Zheng, Jun; Wu, Chia‐Chao; Hou, Yi; Liu, Wen-Chih; Lu, Chien Lin; Zheng, Cai Mei; Lu, Kuo Cheng; You, Chao

doi:10.7150/ijms.51935

Cited by 27 publications

(22 citation statements)

References 149 publications

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“…The presence of comorbid diseases, such as septicemia, diabetes mellitus, chronic respiratory diseases, and cancer, is closely linked to vitamin D deficiency [ 89 ]. In this COVID-19 pandemic, a similarity in prevalent areas and the nature of SARS-CoV-2 infection and vitamin D deficiency was observed [ 9 ], which might explain the importance of vitamin D supplementation in COVID-19 [ 90 ]. Adequate vitamin D supplementation is also required to reduce RAS activity and increase ACE2 concentrations in acute lung injury.…”

Section: Role Of Vitamin D In the Covid-19 Eramentioning

confidence: 99%

Immunological Aspects of SARS-CoV-2 Infection and the Putative Beneficial Role of Vitamin-D

Peng

Liu

Zheng

et al. 2021

IJMS

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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is still an ongoing global health crisis. Immediately after the inhalation of SARS-CoV-2 viral particles, alveolar type II epithelial cells harbor and initiate local innate immunity. These particles can infect circulating macrophages, which then present the coronavirus antigens to T cells. Subsequently, the activation and differentiation of various types of T cells, as well as uncontrollable cytokine release (also known as cytokine storms), result in tissue destruction and amplification of the immune response. Vitamin D enhances the innate immunity required for combating COVID-19 by activating toll-like receptor 2. It also enhances antimicrobial peptide synthesis, such as through the promotion of the expression and secretion of cathelicidin and β-defensin; promotes autophagy through autophagosome formation; and increases the synthesis of lysosomal degradation enzymes within macrophages. Regarding adaptive immunity, vitamin D enhances CD4+ T cells, suppresses T helper 17 cells, and promotes the production of virus-specific antibodies by activating T cell-dependent B cells. Moreover, vitamin D attenuates the release of pro-inflammatory cytokines by CD4+ T cells through nuclear factor κB signaling, thereby inhibiting the development of a cytokine storm. SARS-CoV-2 enters cells after its spike proteins are bound to angiotensin-converting enzyme 2 (ACE2) receptors. Vitamin D increases the bioavailability and expression of ACE2, which may be responsible for trapping and inactivating the virus. Activation of the renin–angiotensin–aldosterone system (RAS) is responsible for tissue destruction, inflammation, and organ failure related to SARS-CoV-2. Vitamin D inhibits renin expression and serves as a negative RAS regulator. In conclusion, vitamin D defends the body against SARS-CoV-2 through a novel complex mechanism that operates through interactions between the activation of both innate and adaptive immunity, ACE2 expression, and inhibition of the RAS system. Multiple observation studies have shown that serum concentrations of 25 hydroxyvitamin D are inversely correlated with the incidence or severity of COVID-19. The evidence gathered thus far, generally meets Hill’s causality criteria in a biological system, although experimental verification is not sufficient. We speculated that adequate vitamin D supplementation may be essential for mitigating the progression and severity of COVID-19. Future studies are warranted to determine the dosage and effectiveness of vitamin D supplementation among different populations of individuals with COVID-19.

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Section: Role Of Vitamin D In the Covid-19 Eramentioning

confidence: 99%

Immunological Aspects of SARS-CoV-2 Infection and the Putative Beneficial Role of Vitamin-D

Peng

Liu

Zheng

et al. 2021

IJMS

Self Cite

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“…According to the above evidence, we put forward the hypothesis that sufficient vitamin D status at the time of infection contributes to an early type I IFN protective response and enhances the innate antiviral immunity to SARS-CoV-2. As the disease progresses, the immunomodulatory activity of vitamin D may actually help to reduce the excessive inflammatory damage observed in severe COVID-19, proving its rationality as an adjuvant treatment [47,65,79]. According to the above evidence, we put forward the hypothesis that sufficient vitamin D status at the time of infection contributes to an early type I IFN protective response and enhances the innate antiviral immunity to SARS-CoV-2.…”

Section: Vit-d Interplay With Antiviral Ifn-imentioning

confidence: 89%

“…The presence of comorbid diseases, such as septicemia, diabetes mellitus, chronic respiratory diseases, and malignancy, is tightly linked to vitamin D deficiency [63]. In the midst of the COVID-19 pandemic, a similarity in prevalent SARS-CoV-2 infection areas and vitamin D deficiency areas has been observed [64], which may show the importance of vitamin D supplementation in COVID-19 [65]. Adequate vitamin D levels are also required in order to reduce RAS activity and increase ACE2 concentrations in acute lung injury.…”

Section: Vitamin D Modulates Ace2 and The Rasmentioning

confidence: 98%

Section: Vit-d Interplay With Antiviral Ifn-imentioning

confidence: 99%

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Putative Role of Vitamin D for COVID-19 Vaccination

Chiu

Zheng

et al. 2021

IJMS

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Severe acute respiratory syndrome coronavirus 2 is a new, highly pathogenic virus that has recently elicited a global pandemic called the 2019 coronavirus disease (COVID-19). COVID-19 is characterized by significant immune dysfunction, which is caused by strong but unregulated innate immunity with depressed adaptive immunity. Reduced and delayed responses to interferons (IFN-I/IFN-III) can increase the synthesis of proinflammatory cytokines and extensive immune cell infiltration into the airways, leading to pulmonary disease. The development of effective treatments for severe COVID-19 patients relies on our knowledge of the pathophysiological components of this imbalanced innate immune response. Strategies to address innate response factors will be essential. Significant efforts are currently underway to develop vaccines against SARS-CoV-2. COVID-19 vaccines, such as inactivated DNA, mRNA, and protein subunit vaccines, have already been applied in clinical use. Various vaccines display different levels of effectiveness, and it is important to continue to optimize and update their composition in order to increase their effectiveness. However, due to the continuous emergence of variant viruses, improving the immunity of the general public may also increase the effectiveness of the vaccines. Many observational studies have demonstrated that serum levels of vitamin D are inversely correlated with the incidence or severity of COVID-19. Extensive evidence has shown that vitamin D supplementation could be vital in mitigating the progression of COVID-19 to reduce its severity. Vitamin D defends against SARS-CoV-2 through a complex mechanism through interactions between the modulation of innate and adaptive immune reactions, ACE2 expression, and inhibition of the renin-angiotensin system (RAS). However, it remains unclear whether Vit-D also plays an important role in the effectiveness of different COVID-19 vaccines. Based on analysis of the molecular mechanism involved, we speculated that vit-D, via various immune signaling pathways, plays a complementary role in the development of vaccine efficacy.

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“…Drugs with potential for inhibiting these overexpressed immunogenic pathways in the tissues invaded by coronaviruses has been a matter of debate since the inception of the pandemic. The effectiveness of NSAIDs such as Indomethacin in COVID-19 coagulopathy, discouraging the SARS viral replication, the inflammasome deactivation, and synergistic inhibition of H5N1 viral infection with representative antiviral drugs, have provided a silver lining in adjuvant COVID-19 therapy [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

Indomethacin for refractory COVID or post-COVID headache: a retrospective study

Krymchantowski¹,

Silva‐Néto²,

Jevoux³

et al. 2021

Acta Neurol Belg

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Background COVID-19, a disease caused by SARS-CoV-2, manifests with headache, both in the acute phase and as a post-infection symptom, which may be refractory to usual analgesics. Objectives Investigate the therapeutic response of refractory COVID or post-COVID headache to indomethacin. Methods This was an observational, retrospective, open and uncontrolled. A sample of 37 patients diagnosed with COVID-19 presenting headache during the acute phase or after the resolution of the disease, with refractoriness to the usual symptomatic medication was treated with indomethacin. Results Of the 37 patients (24 women and 13 men), 29 were migraineurs and 8 had no previous history of headache. The average age was 40.4 ± 9.4 years, ranging from 19 to 65 years. In 26 (70.3%) patients, the onset of headache occurred within 72 h, and in 11 (29.7%), after 10 days of positivity for Sars-CoV-2. After treatment with indomethacin, 36 patients reported greater than 50% headache relief from the third day and 5 became asymptomatic on the fifth day. Conclusions In patients with migraine or no prior history of headache who present with refractory COVID or post-COVID headache to common analgesics, anti-inflammatory drugs, and/or triptans, indomethacin should be considered a therapeutic option.

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Perspective Adjunctive Therapies for COVID-19: Beyond Antiviral Therapy

Cited by 27 publications

References 149 publications

Immunological Aspects of SARS-CoV-2 Infection and the Putative Beneficial Role of Vitamin-D

Immunological Aspects of SARS-CoV-2 Infection and the Putative Beneficial Role of Vitamin-D

Putative Role of Vitamin D for COVID-19 Vaccination

Indomethacin for refractory COVID or post-COVID headache: a retrospective study

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