The neutralisation of the coronavirus has been much discussed in recent weeks, including antiviral medication used for HIV, HCV and anti malarial drugs with variable outcomes (potent antiviral drugs, such as remdesivir, chloroquine, or lopinavir/ritonavir) also convalescent plasma and IgG. However, inflammatory mediators appear to impact the progression of disease in COVID 19 patients.
Viral infection require precise regulation of the innate immunity by inflammatory immune mechanisms but over-activation of these processes can cause immunopathology with further complications to infected patients. Some significant clinical feature or patients with coronaviruses include, dyspnea, hypoxemia, and acute respiratory distress, lymphopenia, and cytokine release syndrome. This suggests that homeostasis of the immune system could play an important role in the development of COVID-19 pneumonia. Some plasma cytokines and chemokines are increased in COVID 19 patients, including IL-1,2,4,7,10,12,13,17, GCSF, MCSF, IP10, MCP-1, MIP-1, hepatocyte growth factor, IFN-γ and TNF-α.
The protective barriers of mast cells of the submucosa in the respiratory tract are activated by the virus and release histamine and protease and later activate IL-1 and IL-33. Could IL-1 receptor antagonists be helpful?
Histamine, as well as affecting vascular and bronchial responses, is increasingly identified with modulation of immune responses, including a variety of lymphocytes, such as T cells. Could antihistamines have beneficial effects on immune dysregulation and tissue remodelling during COVID 19 infection?
Virus particles invade the respiratory mucosa firstly and infect other cells, triggering a series of immune responses and over-activation of lymphocytes by apoptosis or necrosis of infected cells and the production of a cytokine storm causing a systemic T cell response in the patient, which may be associated with the critical condition of COVID-19 patients. COVID 19 attaches to pulmonary host cells by ACE2 then fuses to the membrane and releasing viral RNA. Lower levels of granulocytes are observed in the severe group than the mildly infected.
The development of inflammatory complications may be associated with the genetic individuality of a patient’s innate immune responses, resulting in different phenotypes. Considering the balance of IL-10/IL-12 expression influences the Th1/Th2 responses and imbalance in airway mucosa plays an important role in immune responses to viral infections and asthma development, IL-10 drives a humoral response and IL-12 drives a cytotoxic T cell response. Whereas Th2 responses are linked to the development of atopy, Th1 differentiation is often associated with the pathology of certain autoimmune processes. Patients with asthma viral infections tend to promote a Th2 response and increased eosinophilia exacerbates symptoms of the disease leading to breathing difficulties. Patients with chronic airway inflammatory diseases have impaired or reduced ability to promote Th1 cytotoxic responses to neutralise the virus. Could this be an implication for IL-12 therapy for anti-viral responses in patients not able to clear COVID 19?
In the severe group, CD4+ cells with lower IFN-γ and TNF-α and levels of granzyme B and perforin in CD8+ T cells were higher in the severe group than in the mild group. Could IFNγ as an antiviral therapy, despite its rather unpleasant side effects?
Further, Zinc supplementation showed benefits, shortening the duration of oxygen desaturation, tachypnea, and clinical symptoms in children with pneumonia, showing a Th1 response with the increase of IFNγ and IL-2 cytokines.
Chloroquine also seems to act as a zinc ionophore, thereby allowing extra cellular zinc to enter inside the cell and inhibit viral RNA dependant RNA polymerase.
Please contribute to this discussion.
Suggestions for anti-inflammatory considerations
References
- Marone G, Granata F, Spadaro G, Genovese A, Triggiani M. The histamine-cytokine network in allergic inflammation. J Allergy Clin Immunol. 2003;112(4 Suppl):S83–S88. doi:10.1016/s0091-6749(03)01881-5
- Yan-Rong Guo, Qing-Dong Cao, Zhong-Si Hong, Yuan-Yang Tan, Shou-Deng Chen, Hong-Jun Jin, Kai-Sen Tan, De-Yun Wang, and Yan Yan The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status. Mil Med Res. 2020; 7: 11.
- Zheng, H., Zhang, M., Yang, C. et al. Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients. Cell Mol Immunol (2020). https://doi.org/10.1038
- Front. Pediatr., 14 November 2019 | https://doi.org/10.3389/fped.2019.00431). /s41423-020-0401-3).
- J A Carr, J Rogerson, M J Mulqueen, N A Roberts, and R F Booth. Interleukin-12 exhibits potent antiviral activity in experimental herpesvirus infections. J Virol. 1997 Oct; 71(10): 7799–7803.
- Jorge Alberto Acevedo-Murillo, Miguel Leonardo García León, Verónica Firo-Reyes, Jorge Luis Santiago-Cordova, Alejandra Pamela Gonzalez-Rodriguez2 and Rosa María Wong-Chew, Zinc Supplementation Promotes a Th1 Response and Improves Clinical Symptoms in Fewer Hours in Children With Pneumonia Younger Than 5 Years Old. A Randomized Controlled Clinical Trial. Front. Pediatr., 14 November 2019 | https://doi.org/10.3389/fped.2019.00431
In addressing the mast cell involvement, this paper is very interesting
Gerhard J. Molderings & Britta Haenisch & Stefan Brettner & Jürgen Homann & Markus Menzen & Franz Ludwig Dumoulin & Jens Panse & Joseph Butterfield & Lawrence B. Afrin, Pharmacological treatment options for mast cell activation disease, Naunyn-Schmiedeberg's Arch Pharmacol (2016) 389:671–694
Morrison J, Rathore APS, Mantri CK, Aman SAB, Nishida A, St John AL. Transcriptional Profiling Confirms the Therapeutic Effects of Mast Cell Stabilization in a Dengue Disease Model. J Virol. 2017;91(18):e00617-17. Published 2017 Aug 24. doi:10.1128/JVI.00617-17
Therapeutic strategies include steroids, intravenous immunoglobulin, selective cytokine blockade (eg, anakinra or tocilizumab) and JAK inhibition.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext
I can suggest usage only of 3rd generation antihistamines as they have some in vitro proven anticipatory action by inhibition of LTE.What do you think about the use of celecoxib as IL 6 inhibitor?
Many thanks Muhammad for you suggestions. When considering the suggested current treatments to be administered that are able to truncate this pandemic, the antiviral considerations and anti cytokine storms present as quite separate issues. Were the antibodies that you suggested antiviral or TNF neutralising antibodies to reduce inflammation?
It is thought that convalescent plasma or passive antibody therapy to ameliorate the COVID 19 infection needs to be administered at an early stage of infection. Several different approaches have been considered, including antibodies to SARS and MERS viruses. It was postulated that the measles vaccine may be protective as Chinese children largely receive the vaccine and seemed to be less vulnerable to infection compared to the elder population in the Chinese population. Measles is far more infectious that COVID 19 (RO=12-14 versus RO 2.6).
The antiviral therapy Remdesivir is effective against SARS CoV and MERS CoV and has been deemed available in the US for ‘compassionate use’ for patients infected with COVID 19.
The therapeutic potential of antibody antiviral therapy against COVID 19 has yet to be evaluated.
Russell Beth, Moss Charlotte, George Gincy, Santaolalla Aida, Cope Andrew, Papa Sophie, Van Hemelrijck Mieke (2020) Associations between immune-suppressive and stimulating drugs and novel COVID-19—a systematic review of current evidence ecancer 14 1022
Shereen MA, Khan S, Kazmi A, Bashir N, Siddique R. COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses. J Adv Res. 2020;24:91–98. Published 2020 Mar 16. doi:10.1016/j.jare.2020.03.005
Rosa SGV, Santos WC. Clinical trials on drug repositioning for COVID-19 treatment [Ensayos clínicos de reposicionamiento de medicamentos para el tratamiento de la COVID-19]. Rev Panam Salud Publica. 2020;44:e40. Published 2020 Mar 20. doi:10.26633/RPSP.2020.40
Shanmugaraj B, Siriwattananon K, Wangkanont K, Phoolcharoen W. Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). Asian Pac J Allergy Immunol. 2020;38(1):10–18. doi:10.12932/AP-200220-0773
Kaloyan, I fully agree that 3rd generation antihistamines should be considered but I am not aware of this as common practice in the case of severely affected COVID 19 patients. Are you aware of any clinical applications of this? Thank you for your contribution.
There has been much discussion recently about the possibility of different genotypes influencing the disease outcomes of COVID 19 infection. There are two influences that I would like to present, firstly Immune response cytokine IL-12.
Considering IL12 genotypes and the immune response to COVID 19
Although the therapy of IL-12 for HCV had low efficacy and was poorly tolerated in HCV patients (Pockros et al 2003) are there lessons to learn from HCV infection with regard to COVID 19 infection, particularly when we consider genetic factors? Whereas Th2 responses are linked to the development of atopy, Th1 differentiation is often associated with the pathology of certain autoimmune processes. IL-12 is a key signal of the innate immune system, acts as a bridge between innate and acquired immunity and thus plays a crucial role in the development of antiviral immune responses (Trinchieri 1995, 2003). Its production is important in the generation of cell-mediated immunity against many intracellular pathogens, including bacteria, fungi, protozoans and viruses (Johnson and Sayles 1997, Trinchieri 1998, Trinchieri et al 2003). The cytokine can, however, enhance or inhibit humoral immunity depending on the Ig isotype and the stimulus to antibody formation. IgG2a,b and IgG3 responses are associated with Th1 responses (Germann et al 1995b) and Th2 responses are associated with IgG1 antibodies which are suppressed by IL-12 (Buckanan et al 1995).
The study of patients and the clinical consequences resulting from defects in the IL-12 dependent IFN-g pathway has shed much light on the Th1/Th2 paradigm during immune responses which has largely been based on animal models. (Lammas et al 2000) These patients have mutations of the IL-12 p40, IL-12 receptorb1 and the IFN-g receptor and identification of these mutations gives insight into the mechanisms involved in the human host defence against intracellular pathogens (Dorman and Holland 2000).
The precise role of IL-12 in virus immune responses, in particular in HCV, is poorly understood but its involvement in enhancing the cytotoxic response and the fact that Th1 driven responses are important for HCV clearance suggest that IL-12 is an important factor in the disease. The differentiation of uncommitted T cells, during the induction of a cytotoxic antiviral host response, is characterised by the secretion of lymphokines associated with cell-mediated immunity rather than those secreted during a humoral response. A strong Th1 CD4+ response is also thought to be essential for spontaneous viral clearance and this is facilitated by the expression of IL-12 from macrophages and dendritic cells (Ma X et al 2015, Yu S et al 2015). IL-12 mediates some physiological activities by acting as a potent inducer of IFN-g secretion by Th1 and natural killer cells and is extremely important in the clearance of viraemia.
IL-12 and IFN-g levels are lower in patients with viraemic, chronic HCV than in patients who spontaneously cleared the virus (Sarih et al 2000). Data confirming this finding reported that cellular responses were defective in HCV infected patients with raised levels of cytokines such as IFN-g, IL-2, IL-4 and IL-10 in supernatants of PBMCs after stimulation with PHA and HCV antigens. IL-12 enhanced the immune response of these patients when cell cultures were treated with the cytokine (Fan et al 2000).
Although the production of IL-12 is vital for HCV viral clearance initiating Th1 responses, unregulated and ongoing IL-12 production can result in infection-induced immunopathology and liver damage. When IL-12 production from dendritic cells by microbial products was inhibited infection-induced immunopathology was reduced (Reis e Sousa et al 1999. Yang CM et al 2017).
Polymorphisms in the IL12-B (p40) gene were associated with different outcomes to infection in HCV patients. Also deficiency of the beta-1 chain of the IL-12 receptor (IL-12RB1) has been associated with patients found to have impaired but not abrogated IFN-g secretion. Some of these patients were asymptomatic until adulthood and mycobacterial infections were usually curable (de Jong et al 1998).
Further to this, deficiency of IL-12 has been associated with recurrent episodes of pneumonia with sepsis and other infections in the absence of fevers. A patient with this deficiency has been described as a 3-year-old female with PBMCs that exhibited normal proliferative responses to antigens and was thought to have a defect in the signalling pathways for IL-12B gene activation and expression. Immune responses to tetanus, diphtheria and pneumococcal antigens were normal. There were normal B and T cell phenotypes and immunoglobulin levels were also within normal ranges. The production of IL-12 p75, however, was undetectable and production of IFN-g was reduced. When IFN-g was added to normal control PBMCs and stimulated with Staphylococcus aureus or lipopolysaccharide, IL-12 production was enhanced by up to 6-fold. IL-12B mRNA was undetectable when IFN-g was added to the patient cells in a similar experiment (Haraguchi et al 1998).
Deficiency of the beta-1 chain of the IL-12 receptor (IL-12RB1) has been associated with patients found to have impaired but not abrogated IFN-g secretion. Some of these patients were asymptomatic until adulthood and mycobacterial infections were usually curable (de Jong et al 1998). Functional IL-12 receptors are primarily expressed on activated NK and T cells (Desai et al 1992). IL-12b2 expression is tightly controlled and may provide an important mechanism for the regulation of IL-12 responsiveness (Rogge et al 1997).
Could the polymorphic differences between COVID 19 patients, in particular IL-12 and IL-12 receptors polymorphisms, influence those different phenotypes in response to COVID 19 infection?
Secondly to-
Ethnicity, skin colour, melanin and vitamin D immunity
A marked increase of non-Caucasian ethnicities has been observed of healthcare workers who have succumbed fatally to the COVID 19 virus. With this in mind, a second genetic factor could be considered regarding skin colour and melanin content. Skin type influences vitamin D levels where darker skin has greater amounts of melanin, which competes for UVB photons with 7-dehydrocholesterol (vitamin D making substrate). Several epidemiological studies link higher susceptibility to immune mediated disorders with vitamin D deficiency.
The non-skeletal effects of vitamin D have been of increasing interest with regard to its association with several diseases and, in particular, its role in regulating the immune system at the cellular level. 1,25-dihydoxyvitamin D3, the active form of vitamin D, has a physiological role in immunomodulation targeting several cells of the immune system and is a key factor linking innate and adaptive immunity and both are compromised with vitamin D deficiency. Hypovitaminosis D is associated with several immune and autoimmune disorders in addition to the classical association with osteomalacia.
Several immune cells have the cellular ability to convert 25-hydroxyvitamin D to active 1,25-duhydroxyvitamin D, which promote responses to pathogens in macrophages. Another antimicrobial response is in regulating the maturation of antigen-presenting dendritic cells and this pathway controls T-lymphocyte function. T cells also responds directly to activated vitamin D. Another immunomodulatory function is that cells of the immune system express vitamin D-activating enzymes also enabling the conversion of vitamin D into its active form.
The amount of UV exposure is related to the global UV index is also associated with vitamin D synthesis in skin and thus undergoes activation via a binding protein in the liver and kidney.
As higher levels of melanin inhibit vitamin D synthesis from UV exposure and the currently low UV index in the UK, this may influence the demographic findings of healthcare workers that have succumbed to the virus.
References
· Vitamin D levels, for instance, are associated with thyroid nodule size, which is commented in the paper to influence MIBI uptake by parathyroid cells. Vitamin D receptor (VDR) polymorphisms also alter vitamin D levels and can influence disease.
· Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc. 2012;71(1):50–61. doi:10.1017/S0029665111001650
· Hewison M. Vitamin D and the immune system: new perspectives on an old theme.Endocrinol Metab Clin North Am. 2010;39(2):365–379. doi:10.1016/j.ecl.2010.02.010
· Glass D, Lens M, Swaminathan R, Spector TD, Bataille V. Pigmentation and vitamin D metabolism in Caucasians: low vitamin D serum levels in fair skin types in the UK. PLoS One. 2009;4(8):e6477. Published 2009 Aug 3. doi:10.1371/journal.pone.0006477
· Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet. 1982;1(8263):74–76. doi:10.1016/s0140-6736(82)90214-8
· Jones P, Lucock M, Chaplin G, et al. Distribution of variants in multiple vitamin D-related loci (DHCR7/NADSYN1, GC, CYP2R1, CYP11A1, CYP24A1, VDR, RXRα and RXRγ) vary between European, East-Asian and Sub-Saharan African-ancestry populations. Genes Nutr. 2020;15(1):5. Published 2020 Mar 13. doi:10.1186/s12263-020-00663-3
· Rockell JE, Skeaff CM, Williams SM, Green TJ. Association between quantitative measures of skin color and plasma 25-hydroxyvitamin D. Osteoporos Int. 2008;19(11):1639–1642. doi:10.1007/s00198-008-0620-4
There is another genetic factor that influences Vitamin D synthesis in humans and that may influence COVID 19 infection in a small way but I did not wish to muddy the water of the previous comments on vitamin D synthesis in humans but nevertheless, despite being a rare condition, is a consideration for a small number of individuals. Hereditary Vitamin D Resistant Rickets (HVDRR) is a rare disease caused by mutations in the vitamin D receptor (VDR). The consequence of defective VDR is the inability to absorb calcium normally in the intestine. Perhaps these individuals are particularly vulnerable and should be in the protected groups.
Genotype of vitamin D receptor influencing severity of COVID 19 infection
Having already established that genetic factors determining skin colour may influence disease outcomes to COVID 19 infection, it should also be considered that genetic differences in vitamin D receptor genes (VDR) might influence disease outcomes.
Located on chromosome 12q13.11 in humans, the VDR gene consists of eleven exons. Several polymorphisms of the VDR gene have been identified, but four single-nucleotide polymorphisms (SNPs) of this gene are the ones that have been most studied, namely, BsmI (rs1544410), ApaI (rs7975232), TaqI (T> C; rs731236), and FokI (C> T; rs2228570, formerly known as rs10735810).
There is evidence that complete histamine blockade preventing ARDS in septic animal models. H1 blocker would be benadryl, H2 blocker would be ranitidine, and H3 would be betahistine. Here is the link backing this up: Surgery. 1987 Aug;102(2):350-7.
Successful treatment of adult respiratory distress syndrome by histamine and prostaglandin blockade in a porcine Pseudomonas model.
Sielaff TD, Sugerman HJ, Tatum JL, Blocher CR.
Further to the subject of ethnic variation in COVID 19 infection outcomes.
Another factor in this discussion is that the marked increase of non-Caucasian ethnicities has been observed of healthcare workers who have succumbed fatally to the COVID 19 virus could be related to hypertensive drug treatment regimens, as there is a difference, according to the treatment British Hypertension Society recommendations, for combining blood pressure lowering drugs for different ages and ethnicity, where black patients and older patients tend to be treated with diuretics and calcium channel blockers whereas the younger or non-black patients receive ACEI/ARB and Beta blockers.
In a retrospective study in Hubei province in China, COVID 19 patients, admitted to 9 hospitals in a multi-centre study, between December 31st and February 29th 2020. 1128 hospitalised adult patients with hypertension and diagnosed with COVID 19 were included in the study. There were 188 patients taking ACEI/ARB and 940 not taking ACEI/ARB with a median age of 64 years.
ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB non-users (ACEI/ARB group versus the non-ACEI/ARB group (3.7% vs. 9.8%; P = 0.01)).
- Zhanf P, Zhu L, Cai J, et al. (April 2020). "Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19". Circ Res. doi:10.1161/CIRCRESAHA.120.317134.PMID 32302265.
- Azra Mahmud, John Feely, Choice of First Antihypertensive: Simple as ABCD? , American Journal of Hypertension, Volume 20, Issue 8, August 2007, Pages 923–927.
This is NOT a medical advice and must be used for educational purpose and clinical studies development only.
Letter to: Cytokine release syndrome in severe COVID-19
Repurposing of bazedoxifene to prevent cytokine storm in COVID-19 patients
Prof. Jan Brábek, PhD, Daniel Rosel, PhD, Michael Fernandes MD
We congratulate John B. Moore and Carl H. June on the recent article 1, describing cytokine release syndrome (CRS) in severe COVID-19 and the role IL6 signaling inhibition with humanized IL6 receptor antibodies in prevention of CRS. 1 The authors may have missed that bazedoxifene acetate (Conbriza, Pfizer) inhibits IL-6 signaling at therapeutic doses.2 The approved daily dose of bazedoxifene, indicated for osteoporosis, should effectively inhibit IL-6 signaling and this way potentially prevent or mitigate Acute Respiratory Distress Syndrome (ARDS) COVID-19 patients. Compared to the monoclonal antibodies, tocilizumab, sarilumab, and siltuxizumab, bazedoxifene has additional advantages related to possible effectiveness against COVID-19 entry and replication 3, as well as scale-up, delivery and cost. At this time, and as implied by Moore and June 1, addressing ARDS, the proximate cause of mortality, with available agents, takes precedence over the development of antiviral antibiotics and vaccines.
We declare no competing interests.
*Jan Brábek, Daniel Rosel, Michael Fernandes [email protected] Charles University, Prague, Czech Republic (JB, DR); and Biotechnology and Biomedicine Center of the Academy of Sciences (BIOCEV) (JB, DR) and Charles University, Vestec, Czech Republic (JB, DR), Medbase, Chapel Hill, NC 27514, USA (MF)
References
1. Moore JB and June CH. Cytokine release syndrome in severe COVID-19. Science 2020; 10.1126/science.abb8925
2. Thilakasiri P, Huynh J, Poh AR, et al. Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth. EMBO Mol Med. 2019; 11: e9539.
3. Zhou Y, Hou Y, Shen J, et al. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discovery. 2020; 6:14.
In a recent email communication from Dr Stephane Arminjon who piloted a COVID 19 therapy using antihistamine to dampen the hyper inflammation in patients with COVID 19 infections, it is reported that this therapy approach is promising but requires larger cohorts to confirm the implied significance. I have attached his report. This is extremely exciting development and hope that further trials will be able take place.
Can we manage prophylactic therapy in COVID-19 patients to prevent severe illness complications?
https://www.scielo.br/pdf/jvb/v19/en_1677-5449-jvb-19-e20200057.pdf
There are about 300 clinical trials being carried out as antiviral therapies for COVID 19 infection. Post or pre exposure prophylaxis of rifampicin and oseltamivir is recommended by WHO for people at high risk of COVID 19 infection during the pandemic.
Some obvious pre-exposure-prophylaxis considerations should be vitamins D and C to ensure strong and effective immune responses to neutralise the virus.
Chloroquine and hydroxychloroquine are hugely controversial at the moment due to hasty and inappropriate understanding of literature from public leaders in USA and there are no statistically significant results for the study and serious complications indicated, including, cardiac toxicity, QT prolongation, and ventricular arrhythmias. Clinical trials continue in China with some promising indications but not statistically significant.
Nitrazonxanide combined with azithromycin is tentatively suggested as a safe and available regimen to consider as a preventative antiviral therapy. Tizoxanide is the active metabolite of nitrazonxanide and is potent against COID 19 in vitro and has broad-spectrum antiviral activity.
Further trials are required to assess the efficacy of Invermectin as an antiviral against COVID 19. It is actually an antiparasitic but was able to reduce COVID 19 viral RNA and disrupts the immune invasion mechanism.
Antihistamines have beneficial effects on immune dysregulation and tissue remodelling during COVID 19 infection? The protective barriers of mast cells of the submucosa in the respiratory tract are activated by the virus and release histamine and protease and later activate IL-1 and IL-33. Histamine, as well as affecting vascular and bronchial responses, is increasingly identified with modulation of immune responses, including a variety of lymphocytes, such as T cells. A recent trial took place in France where antihistamines were given to patients displaying COVID 19 symptoms and none developed severe infection in the cohort. Third generation antihistamine is an over the counter drug that is extremely well tolerated.
ARBs are also being investigated as inhibitors of viral attachment to ACE2. Antithrombotic drugs are also an option to inhibit the thrombotic events observed in the very most severely affected patients who die from the virus.
High UV index known to neutralise the virus so just a few options to try.
I'm very pleased to notice that Meriel Raymond, Gemma Ching A Sue and Oliver Van Hecke, associated with Oxford University, are also writing about the role of mast cells and histamine in the cytokine storm of COVID 19 infection and have produced this early paper considering antihistamines as mast cell stabilisers.
https://www.cebm.net/covid-19/mast-cell-stabilisers-leukotriene-antagonists-and-antihistamines-a-rapid-review-of-effectiveness-in-covid-19/
The idea that the cytokine and chemokine storm is related to the degranulation of mast cells resembles an excellent idea. The treatment of MCAS includes not only the application of antihistamines (H1-H4) but also several other drugs such as imatinib or polyphenols. However, the question still needs to be asked why the mast cells degranulate in Covid-19. If we assume that IgE is the trigger, an infection should already be present (see https://link.springer.com/chapter/10.1007%2F978-3-319-13725-4_1). Therefore, I am thinking about alternative mast cell activation pathways. A helpful article about Non-IgE mediated mast cell activation can be found at https://www.sciencedirect.com/science/article/abs/pii/S0014299915301448?via%3Dihub . Thus, there is a further possibility to activate mast cells by Toll-like receptors (TLRs https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579400/ ).
In addition to the suggestions already made, I, therefore, suggest the inhibition of TLRs to manage the cytokine storm. The approach appears to be feasible as an option to treat rheumatoid arthritis https://onlinelibrary.wiley.com/doi/full/10.1002/eji.201546123
Thank you so much, Ruediger, for your contribution. I made a few notes on mast cell activation, particularly IgG involvement as over the last year mast cells have been a particular interest for me and am preparing a paper on the subject.
Mast cells
They originate from CD38+, being granulocytes derived from myeloid stem cells. MCs are also associated with neuro-immune systems. As innate immune cells, MCs are phenotypes that are tuned by cytokines and other micro-environmental stimuli. They also play a role in transplantation immunology but this will not be further discussed in this review.
As members of the innate immune system, MCs are located in places like skin, lung, and intestinal mucosa, which are in close contact to the outside world and they have an immediate activated response to parasite infections and antigens involved in allergies. In the case of parasites and allergens, these long-lived MCs defend against parasites maintaining an immune protection on the physical barriers in the body and are activated by the antigens. The response is mediated by a cross linking of FceR1 by immunoglobulin E (IgE), which results in the degranulation of the MCs. This particular linkage is used in MC detection by applying high infinity IgE. Staining the MC granules with toluene blue also characterises the cells.
There are a wide variety of receptors expressed on the surface of MCs that enable them to be activated by several different ligands, such as, endogenous cytokines, IgE, TLR ligands and IgG immune complexes. The inflamed tissue contains many of these ligands. A number of mediators including chymase, tryptase, histamine and other cytokines and chemokines are released, dependent on the route of activation.
An in vivo experiment with rats found that IL-3 wa involved in the recruitment of MCs and there were differential effects, dependant on the target tissue and time of exposure to the chemoattractant (de Cássia Campos MR 2014). Other mediators that stimulate MCs and trigger degranulation, proliferation and release of mediators include, IgG, complement components, TLR ligands, neuropeptides, cytokines, chemokines as well as other inflammatory products. Migration and differentiation are also stimulated by these inflammatory components. Thus the true versatility of MCs is recognised through them responding to a wide repertoire of different stimuli and not just IgE involvement (Yu Y 2016).
The MRGPRX2 MC receptor is important in the activation of MCs by peptide stimuli with abundant positive charges and aromatic/aliphatic amino acids (Lu L 2017).
The activated MC response results in the release of a broad spectrum of proinflammatory mediators, proteolytic enzymes and chemotactic factors that attract other immune cells. Proteolytic induce rapid inflammation and tissue remodelling.
MCs also are important in wound healing releasing factors and promote the recruitment of leukocytes, platelet activation and fibrogenic processes. Although the pathogenesis of RA is not fully understood, joint destruction possibly occurs due to the recruitment of neutrophils and monocytes that facilitate the damage of joint related cartilage when they activate osteoclasts. Histamine is a mediator that is involved in the activation of osteoclasts.
Clearly, in the case of allergies this immune response is detrimental and can cause asthma, even promote anaphylaxis. The MC is rich in granules of histamine and heparin, all-important in the fenestration of epithelium to enable other immune cells, such as, lymphocytes to migrate to the source of supposed infection. Other mediators of immune response from MC granules are leukotrienes causing shortness of breath, prostaglandins, tryptase, interleukins, heparin and TNF-alpha (Jennings S 2014), (Afrin LB 2013), (Valent P 2012), (Theoharides TC 2015).
MCs promote anti-inflammatory mediators as well as proinflammatory processes. They can act as antigen presenting cells and express a large array of co-stimulatory molecules. MCs are able to tolerate the introduction of some antigens without eliciting an inflammatory immune response in certain sites of the human body, described as having immune privilege to tissues with T-regulatory cells and are essential elements in fibrotic conditions.
In allergic responses, MCs are a potential source of chemokines and cytokines, important in inflammation. As well as IgE activation, MCs can be activated by Toll-like receptors and/or IL-1, which can be inhibited by IL-37 whereas IL-36 is a powerful proinflammatory cytokine (Gallenga CE 2019). IL-1 activates the release of inflammatory chemical mediators from MCs.
There are many known triggers for MC activation in addition to Infections (viral, bacterial or fungal)-
· Stress: emotional, physical, including pain
· Stress: environmental (i.e., weather changes, pollution, pollen, pet dander, etc.)
· Food or beverages, including alcohol
· · Heat, cold or sudden temperature changes
· Exercise
· Fatigue
· Drugs (opioids, NSAIDs, antibiotics and some local anaesthetics) and contrast dyes
· Natural odours, chemical odours, perfumes and scents
· Venoms (bee, wasp, mixed vespids, spiders, fire ants, jelly fish, snakes, biting insects, such as flies, mosquitos and fleas, etc.)
· Mechanical irritation, friction, vibration
· Sun/sunlight
Typical symptoms experienced during mast cell activation in allergy are flushing; itching, diarrhoea and hypotension are all mediated by histamine. Leukotrienes cause shortness of breath and prostaglandins are responsible for pain, brain fog, cramping and also flushing. In addition, MCs induce cytokines that cause fatigue, weight loss and enlarged lymph nodes. MCs are also implicated in autoimmune pathology as well..
Perhaps patient histamine levels may be used as an early indication of COVID 19 disease severity or outcome by measuring the COVID 19 patient levels of histamine in serum and urine to assess the possible degree of mast cell involvement in the cytokine storm.
Thanks for the update, Annwyne, and the helpful article. I am interested in mast cells because we are currently working together with a patient organization (MCAS Hope) and two clinics (Charité and RWTH Aachen University) to create a Big Data patient registry for MCAS. We are also working on the exploitation of many scientific articles related to MCAS using Natural Language Processing / Artificial Intelligence to find patterns and trends in MCAS.
I am overwhelmed by the diversity of mast cells and the fact that they are presumably involved in the course of almost all diseases, including, of course, Covid-19. Actually, such a database should also be created for Covid-19...
Mast cells, Th17 cells, Vitamin D and Vitamin D receptors
When considering the T cell response to COVID 19 infection and the T-cell differentiation, other pathways must be considered in addition to Th1 and Th2 driven responses. Mast cell derived cytokines are implicated in Th17 cells activity while Th17 cells promote mast cell proliferation.
In the case of HIV infection Th17 cells can be reservoirs of the virus in patients taking antiretroviral therapy contributing to the latency of HIV infection.
1,25-Dihydroxyvitamin D3(1,25(OH)2D3), the active form of vitamin D, has emerged as a direct regulator of immune system function in humans. Important mechanisms involving the human immune system are mediated through the nuclear receptor, vitamin D receptor (VDR) via the non-canonical processes of vitamin D binding to the receptor. This receptor is expressed by macrophages, dendritic cells and activated T cells. Vitamin D is able to prevent autoimmune inflammatory diseases, particularly by supressing Th17 cells as accumulating reports demonstrated that 1,25(OH)2D3 possessed anti-inflammatory activity on Th17 cells to maintain immunologic homeostasis. Indeed, the active form of Vitamin D directly inhibits Th17 differentiation. VDR is elevated in Th17 cells.
Human memory Th17 Cell populations change Into anti-inflammatory cells with regulatory capacity upon exposure to active Vitamin D metabolite (1,25(OH)2D3).
Th17 cells are a subset of CD4+ T helper cells that produce IL-17. Th17 has an important role in the human immune system by in the host defence against infection but also considered key in the development of autoimmune inflammatory disorders. Loss of h17 can result in chronic infections. They have immunosuppressive properties that decrease the antiviral response to infections, such as HIV and the loss of Th17 can result in a loss of balance between Th17 and Treg cells. IL21 encourages Th17 differentiation and proliferation. IL-17A expression is up regulated by Th17 cells, at sites of inflammation in several autoimmune diseases. IL-17 is a pleiotropic cytokine, where the one gene exhibits two or more phenotypic traits.
Vitamin D is considered to supress IL-17A production in T cells in some conditions (RA, MS, colitis). IL-6 and IL-22 expression may also be down regulated from naive and memory CD4+T cells. Confusingly, Th17 cells are not always pathogenic unless exposed to IL-23.
A high number of CCR6+ Th17 cells were observed in a severely affected COVID 19 patient supporting the hypothesis that Th17 cells are important factors in the cytokine storm in the disease. Elevated Th17 cells and enhanced IL-17 pathways were a factor in patients with MERS-CoV and SRS-CoV. In H1N1 infection in mice acute lung injury was a factor induced by IL-17 expression.
There are some anti Th17 and IL17 blockades in antibody form currently being trialled.
IL-17 is increased in patients infected with COVID 19, in intensive care, as opposed to those not in intensive care. An anti IL-17 drug is currently being trialled in China, ixekizumab a drup developed for the treatment of psoriasis.
In the case of HIV neutralisation of IL-17 eliminates virus infected cells thus enhancing, viral clearance and boosting the ability of cytotoxic T cells to lyse infected cells. Th1 cytokines (IFNϒ) driving a Th1 response have a powerful antiviral function that inhibits Th17 differentiation. Could this be a similar scenario with COVID 19?
Zhang, H., Shih, D. Q., & Zhang, X. (2013). Mechanisms underlying effects of 1,25-Dihydroxyvitamin D3 on the Th17 cells. European journal of microbiology & immunology, 3(4), 237–240. https://doi.org/10.1556/EuJMI.3.2013.4.1
Josset, L., Menachery, V. D., Gralinski, L. E., Agnihothram, S., Sova, P., Carter, V. S., Yount, B. L., Graham, R. L., Baric, R. S., & Katze, M. G. (2013). Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus. mBio, 4(3), e00165-13. https://doi.org/10.1128/mBio.00165-13Hamzaoui, Agnes; Berraïes, Anissa; Hamdi,
Besma; Kaabachi, Wajih; Ammar, Jamel; Hamzaoui, Kamel (November 2014). "Vitamin D reduces the differentiation and expansion of Th17 cells in young asthmatic children". Immunobiology. 219 (11): 873–879.doi:10.1016/j.imbio.2014.07.009. ISSN 0171-2985.PMID 25128460.
Histamine has a dichotomous nature of promoting inflammatory and regulatory responses contributing to pathological processes that promotes vascular and tissue changes and has high chemo attractant activity. The stimulus for histamine induces the expression of IL-17 in Th17 cells and activation of lymphocytes in some inflammatory conditions.
The pleiotropic effects of histamine are mediated by 4 G-protein coupled histamine receptors (H1-4). Conformations of these receptors coexist in equilibrium and are stabilized in their active form by agonists. The expression of these receptors differentiates according to the differentiation of the cell and influences provided buy the microenvironment. The histamine receptor effects can be determined by genetics but also gut micro biota, aging, gender and other diseases.
Th1 and Th2 balance is directly regulated by histamine. HR1 is important in promoting Th1 responses whereas HR2 promotes Th2 profiles and allergic lung inflammation is associated with the recruitment of Th2 cells. Interestingly, activated Th2 is shown to promote humoral immunity and promotion of IgE production and sometimes, aberrant immune responses.
HR2 also increases IL-10 production, also increasing the humoral response to infection.
Activation of HR1 and HR2 are associated with mast cell and basophil-mediated disorders, such as, allergy. HR1 antagonism is important in reducing inflammation in asthma and H2 deficiency is known to worsen lung inflammation. Could this be further evidence for the use of antihistamine strategies in COVID 19 infection therapy?
Curiously, the aging process is a factor that impairs expression or activity of HRs and enzymes HDC and DAO may contribute to the progression of allergic reactions and various neurodegenerative disorders. Chronic itching occurs in the elderly as changes in immunology and physiology change with age.
Already previously discussed that mast cells are present in the protective barriers of the submucosa in the respiratory tract are activated by the virus and release histamine and protease and later activate IL-1 and IL-33. Histamine, as well as affecting vascular and bronchial responses, is increasingly identified with modulation of immune responses, including a variety of lymphocytes, such as T cells. Are antihistamines a beneficial therapy on immune dysregulation and tissue remodelling during COVID 19 infection?
One test that may be used as an indication of COVID 19 disease outcome would be to measure the levels of histamine in serum and urine at an early stage of the infection.
Branco, A., Yoshikawa, F., Pietrobon, A. J., & Sato, M. N. (2018). Role of Histamine in Modulating the Immune Response and Inflammation. Mediators of inflammation, 2018, 9524075. https://doi.org/10.1155/2018/9524075
Liu C, Zhou Q, Li Y, Garner L, Watkins S et al. Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. ACS Cent. Sci. 2020, 6, 315−331. In https://pubs.acs.org/doi/10.1021/acscentsci.0c00272.
Cynthia Liu et al., provides an overview of published information on global research and development of coronavirus-related therapeutic agents and preventive vaccines based on the extensive CAS content collection, with a focus on patents. It includes an overview of coronavirus morphology, biology, and pathogenesis with a particular focus on antiviral strategies involving small molecule drugs, as well as biologics targeting complex molecular interactions involved in coronavirus infection and replication.
The drug-repurposing effort summarized in this report is focused primarily on agents currently known to be effective against other RNA viruses including SARS-CoV, MERS-CoV, influenza, HCV, and Ebola as well as antiinflammatory drugs. The potential impact of biologics for treatment of coronavirus infections is promising and includes a wide variety of options including bioengineered and vectored antibodies, cytokines, and nucleic acid-based therapies targeting virus gene expression as well as various types of vaccines. The information provided in this report provides a strong intellectual groundwork for support of ongoing research and development for discovery and development of therapeutic agents and vaccines for treatment of COVID-19 and coronavirus-related diseases. Because of limited space, this report devotes minimal attention to current efforts involved in advancing more efficient and accurate COVID-19 diagnosis methods and products. Novel infectious diseases resulting from RNA viruses subject to mutation and genetic recombination, as well as cross-species transmission, will continue to present a serious global health threat, as exemplified by COVID-19.
Despite two former major outbreaks of coronavirus infections causing the SARS and MERS respiratory illnesses, the world remains underprepared to effectively manage the current COVID-19 outbreak, as evidenced by the fact that COVID-19 has resulted in thousands of deaths worldwide. A concerted effort to develop effective drugs and vaccines against existing and potential future coronavirus infections and other highly pathogenic virus outbreaks is necessary to reduce overwhelming impacts on human life and worldwide healthcare systems. Given the costly and arduous process involved with clinical drug development, the outbreak of COVID-19 further highlights the value of developing relatively broad-spectrum antiviral drugs and the importance of applying innovative approaches such as artificial intelligence to facilitate drug discovery.
Given the lengthy process of new drug development, the current strategy of drug repurposing has become one of the chosen solutions for immediate treatment of SARS-CoV-2 infected individuals. Long-term drug development goals for the pharmaceutical industry include identification of inhibitors aimed at the replication or infection processes associated with SARS-CoV-2 or other related coronaviruses, as well as the symptomatic results of their infections leading to severe disease and/or death. The summarized lists, contained in this report, of small molecule compounds, and additional descriptions of biologics with properties suitable for inhibiting several key coronavirus proteins, could serve as information starting points for drug development.
Since vaccines are crucial for prevention of coronavirus-related epidemic diseases in the future, it is reassuring that a number of innovative strategies are already being deployed. Four MERS coronavirus DNA vaccine candidates began phase 1 clinical trials in September of 2019,56 and Moderna Inc. released its first batch of mRNA-1273 in February of 2020, which is an mRNA vaccine against SARSCoV-2 ready for phase 1 study in the United States.55
Additional collaboration in the areas of antiviral discovery processes and clinical trial performance will enhance patients’ access to drug candidates with improved therapeutic potential and ideally reduce the amount of time required to bring these drugs to market. The abundance of publications and the rapid publication rate associated with the SARS-CoV-2 virus-related disease outbreak, as illustrated in this report, are indicative of the intense effort by research institutes and pharmaceutical industries to address both molecular mechanisms and therapeutic routes useful for treating current and future coronavirus outbreaks.
Thanks.
This review is a compilation of many of our recent discussions, called 'The perfect Storm'.
Could antihistamines be used to reduce the hyperinflammatory cytokine storm of mast cell activation after SARSCoV 2 infection when administered early in the infection? Could this be as effective as dexamethasone in the severely affected?
Some centres have trialled this and reported it to be successful but have not published the results yet. Several antihistamines are well tolerated and not expensive.
It is truly excellent news about a vaccine against COVID 19 but until this is fully implemented in the global population there may be a drug to mitigate the severity of COVID 19 complications.
There is some evidence and conceptual thinking in immunology about the benefit of reducing mast cell expression of histamine and thus reducing the severity of COVID 19 symptoms by administering antihistamine drugs when early symptoms of a SARSCoV-2 infection are observed and a positive test for the virus infection. Antihistamines are readily available without prescription and like dexamethasone for severe symptoms, may reduce severity of some COVID 19 symptoms and reduce the need hospital admissions in some patients, particularly progression to alveolar inflammation. Should we add this suggestion to the advice about vitamin D replacement?
Resident mast cells are activated during COVID 19 infection and release histamine, which is important in the inflammatory symptoms observed.
Although mast cell activation and release of chemicals, including histamine, is important to the cytokine driven T-cell differentiation as the adaptive response, expression of histamine can disrupt the homeostasis of the immune system and play an important role in the development of COVID-19 pneumonia, contributing to some of the severe symptoms of alveolar inflammation leading to hypoxia.
A centre in France has already tried this concept on a group of patients who were positive for COVID 19, with significant success.
Just as Dexamethasone has been repurposed as anti-inflammatory medication for severe COVID 19 symptoms perhaps ‘off the self’ antihistamines could be taken for early symptoms.
As an example, there are no officially approved drugs or vaccine to treat dengue disease, MC stabilisation can be achieved with the antihistamine drug ketotifen reversed many of the responses due to MC activation, including reducing the effects of histamine.
If this treatment regimen proves to be successful in some patients, this would be of great advantage in reducing the severity of the pandemic and reduce the need for hospitalisation.
As most patients in the UK, who have symptoms or test positive, do not see a GP but are encouraged to phone 111 or ask for an ambulance with breathing difficulties, how can patients be advised to trial this antihistamine regimen? Like the public information about vitamin D, should everyone be advised to try this?
How can we test this hypothesis using existing products (Loratadine, Cetirizine)?
How can we test this?
My suggestion would be that patients testing positive for COVID 19 would be advised to take antihistamine (unless otherwise contraindicated previously by clinician), patients may already have started to have symptoms before diagnosis so to take the OTC medication when testing positive for COVID 19 or the onset of symptoms, whichever came first. Patients contacting the 111-phone service could be advised to take an OTC antihistamine along with the other advice already given to take Paracetamol and vitamin D.
My suggestion is that households be advised to have the OTC antihistamines in their homes in case of a positive diagnosis. I do not suggest that the medication would inhibit infection at all but just would reduce the severity of some of the symptoms caused by the action of histamine, such as, dyspnoea and hypoxia in some patients.
Viral load will probably not be affected by this therapy so this would have to be monitored. The dosage of the normal daily dose may need to be greater than that stated on the packets. Severe allergic reactions sometimes require four tablets (one a day) to be taken as the maximum dose.
The official advice from the NHS Specialist Pharmacy Service says that hay fever sufferers are safe to take antihistamine products, if infected with the virus. All OTC or non-prescription drugs refer to medicine that you can buy without a prescription. They are safe and effective when you follow the directions on the label or as directed by your health care professional.
The concept does seem far too simplistic to be helpful but the immunology theory does hold up as worth a try.