Immunomodulatory agents for COVID-19 treatment: possible mechanism of action and immunopathology features.

The novel coronavirus pandemic has emerged as one of the significant medical-health challenges of the current century. The World Health Organization has named this new virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first detection of SARS-CoV-2 in November 2019 in Wuhan, China, physicians, researchers, and others have made it their top priority to find drugs and cures that can effectively treat patients and reduce mortality rates. The symptoms of Coronavirus Disease 2019 (COVID-19) include fever, dry cough, body aches, and anosmia. Various therapeutic compounds have been investigated and applied to mitigate the symptoms in COVID-19 patients and cure the disease. Degenerative virus analyses of the infection incidence and COVID-19 have demonstrated that SARS-CoV-2 penetrates the pulmonary alveoli's endothelial cells through Angiotensin-Converting Enzyme 2 (ACE2) receptors on the membrane, stimulates various signaling pathways and causes excessive secretion of cytokines. The continuous triggering of the innate and acquired immune system, as well as the overproduction of pro-inflammatory factors, cause a severe condition in the COVID-19 patients, which is called "cytokine storm". It can lead to acute respiratory distress syndrome (ARDS) in critical patients. Severe and critical COVID-19 cases demand oxygen therapy and mechanical ventilator support. Various drugs, including immunomodulatory and immunosuppressive agents (e.g., monoclonal antibodies (mAbs) and interleukin antagonists) have been utilized in clinical trials. However, the studies and clinical trials have documented diverging findings, which seem to be due to the differences in these drugs' possible mechanisms of action. These drugs' mechanism of action generally includes suppressing or modulating the immune system, preventing the development of cytokine storm via various signaling pathways, and enhancing the blood vessels' diameter in the lungs. In this review article, multiple medications from different drug families are discussed, and their possible mechanisms of action are also described.

Potential implications of six American Indian patients with myopathy, statin exposure and anti-HMGCR antibodies.

OBJECTIVES: Statin-associated autoimmune myopathy is a rare condition associated with the formation of autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Underlying environmental and genetic risk factors remain poorly understood. American Indians have high rates of cardiovascular disease and associated co-morbidities that require lipid-lowering therapies. We observed this autoimmune myopathy in a series of American Indian statin users in rural Arizona. METHODS: We reviewed the charts of six American Indian patients with statin-associated autoimmune myopathy. We provide an illustrative case in addition to summaries of clinical presentations and treatment courses. RESULTS: This is the first report of statin-associated autoimmune myopathy in American Indians. These cases were all identified at the same geographically isolated hospital that exclusively serves an American Indian population with only 1800 statin users. There is relatively low migration. Each case was consistent with the previously described classical presentations for the disease. All six of our cases had diabetes and developed myopathy on high-dose atorvastatin, often with a recent change in statin type or dose. CONCLUSION: Providers serving American Indians need to be aware of the possibility of statin-associated autoimmune myopathy and familiar with its presentation. Larger, inclusive, population-based investigations are needed to elucidate risk factors for this condition, in particular the potential interactions between predisposing HLA alleles, diabetes and specific statin exposures. This is necessary to identify effective and safe lipid-lowering medications.

Influenza Vaccine Effectiveness and Statin Use Among Adults in the United States, 2011-2017.

BACKGROUND: Statin medications have immunomodulatory effects. Several recent studies suggest that statins may reduce influenza vaccine response and reduce influenza vaccine effectiveness (VE). METHODS: We compared influenza VE in statin users and nonusers aged ≥45 years enrolled in the US Vaccine Effectiveness Network study over 6 influenza seasons (2011-2012 through 2016-2017). All enrollees presented to outpatients clinics with acute respiratory illness and were tested for influenza. Information on vaccination status, medical history, and statin use at the time of vaccination were collected by medical and pharmacy records. Using a test-negative design, we estimated VE as (1 - OR) × 100, in which OR is the odds ratio for testing positive for influenza virus among vaccinated vs unvaccinated participants. RESULTS: Among 11692 eligible participants, 3359 (30%) were statin users and 2806 (24%) tested positive for influenza virus infection; 78% of statin users and 60% of nonusers had received influenza vaccine. After adjusting for potential confounders, influenza VE was 36% (95% confidence interval [CI], 22%-47%) among statin users and 39% (95% CI, 32%-45%) among nonusers. We observed no significant modification of VE by statin use. VE against influenza A(H1N1)pdm09, A(H3N2), and B viruses were similar among statin users and nonusers. CONCLUSIONS: In this large observational study, influenza VE against laboratory-confirmed influenza illness was not affected by current statin use among persons aged ≥45 years. Statin use did not modify the effect of vaccination on influenza when analyzed by type and subtype.

Statin-associated immune-mediated myopathy: biology and clinical implications.

PURPOSE OF REVIEW: In the last 6 years, our understanding of statin-associated myopathy expanded to include not only a toxic myopathy with limited and reversible side-effects but also an autoimmune variety in which statins likely induce an autoimmune myopathy that is both associated with a specific autoantibody and responsive to immunosuppression and immune modulation. This review widens the reader's understanding of statin myopathy to include an autoimmune process. RECENT FINDINGS: Statin-associated immune-mediated myopathy provides an example of an environmental trigger (statins) directly implicated in an autoimmune disease associated with a genetic predisposition as well as potential risk factors including concomitant diseases and specific statins. Given a median exposure to statins of 38 months, providers should be aware that anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) myopathy may occur even after several years of statin exposure. SUMMARY: It is important for the reader to understand the clinical presentation of statin-associated immune-mediated myopathy and the difference in its clinical presentation to that of statins as direct myotoxins. Prompt recognition of such an entity allows the clinician to immediately stop the offending agent if it has not already been discontinued as well as to recognize that statin rechallenge is not a likely option, and that prompt treatment with immunosuppression and/or immunomodulation is usually of enormous benefit to the patient in restoring muscle strength and physical function. VIDEO ABSTRACT.

Statin-Associated Autoimmune Myopathy: A Systematic Review of 100 Cases.

BACKGROUND: Statins are a group of drugs that reduce the levels of triglycerides and cholesterol in blood by inhibiting HMG-CoA reductase, an enzyme involved in rate limiting step in cholesterol synthesis. About 2-20% patients on statins develop toxic myopathies, which usually resolve on discontinuation of statin. More recently, an immune-mediated necrotizing myopathy has been found to be associated with statin use which in most cases requires treatment with immunosuppressants. OBJECTIVE: To perform a systematic review on published case reports and case series of statin-associated autoimmune myopathy. METHODS: A comprehensive search of PUBMED, EMBASE, Cochrane library and ClinicalTrials.gov databases was performed for relevant articles from inception until March 19, 2016 to identify cases of statin-associated necrotizing myopathy and characterize their symptoms, evaluation and response to treatment. RESULTS: A total of 16 articles describing 100 patients with statin-associated autoimmune myopathy were identified. The mean age of presentation was 64.72 years, and 54.44% were males. The main presenting clinical feature was proximal muscle weakness, which was symmetric in 83.33% of patients. The mean creatine kinase (CK) was 6853 IU/l. Anti-HMG-CoA reductase antibody was positive in all cases tested (n = 57/57, 100%). In patients with no anti-HMG-CoA antibody results, diagnosis was established by findings of necrotizing myopathy on biopsy. Among the 83 cases where muscle biopsy information was available, 81.48% had necrosis, while 18.51% had combination of necrosis and inflammation. Most (83.82%) patients received two or more immunosuppressants to induce remission. Ninety-one percent had resolution of symptoms after treatment. CONCLUSION: Statin-associated necrotizing myopathy is a symmetric proximal muscle weakness associated with extreme elevations of CK. It is common in males and can occur after months of statin use. It is associated with necrosis on muscle biopsy and the presence of anti-HMG-CoA reductase antibodies. It usually requires discontinuation and immune suppression for resolution. Rechallenge with statin is unsuccessful in most cases.

Absence of anti-HMG-CoA reductase autoantibodies in severe self-limited statin-related myopathy.

INTRODUCTION: Patients with self-limited statin-related myopathy improve spontaneously when statins are stopped. In contrast, patients with statin-associated autoimmune myopathy have autoantibodies recognizing 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) and usually require immunosuppressive therapy to control their disease. On initial presentation, it can sometimes be difficult to distinguish between these 2 diseases, as both present with muscle pain, weakness, and elevated serum creatine kinase (CK) levels. The goal of this study was to determine whether patients with severe self-limited statin-related myopathy also make anti-HMGCR autoantibodies. METHODS: We screened 101 subjects with severe self-limited cerivastatin-related myopathy for anti-HMGCR autoantibodies. RESULTS: No patient with severe self-limited cerivastatin-related myopathy had anti-HMGCR autoantibodies. CONCLUSION: Anti-HMGCR autoantibody testing can be used to help differentiate whether a patient has self-limited myopathy due to cerivastatin or autoimmune statin-associated myopathy; these findings may apply to other statins as well. Muscle Nerve 54: 142-144, 2016.

Statin-conferred enhanced cellular resistance against bacterial pore-forming toxins in airway epithelial cells.

Statins are widely used to prevent cardiovascular disease. In addition to their inhibitory effects on cholesterol synthesis, statins have beneficial effects in patients with sepsis and pneumonia, although molecular mechanisms have mostly remained unclear. Using human airway epithelial cells as a proper in vitro model, we show that prior exposure to physiological nanomolar serum concentrations of simvastatin (ranging from 10-1,000 nM) confers significant cellular resistance to the cytotoxicity of pneumolysin, a pore-forming toxin and the main virulence factor of Streptococcus pneumoniae. This protection could be demonstrated with a different statin, pravastatin, or on a different toxin, α-hemolysin. Furthermore, through the use of gene silencing, pharmacological inhibitors, immunofluorescence microscopy, and biochemical and metabolic rescue approaches, we demonstrate that the mechanism of protection conferred by simvastatin at physiological nanomolar concentrations could be different from the canonical mevalonate pathways seen in most other mechanistic studies conducted with statins at micromolar levels. All of these data are integrated into a protein synthesis-dependent, calcium-dependent model showing the interconnected pathways used by statins in airway epithelial cells to elicit an increased resistance to pore-forming toxins. This research fills large gaps in our understanding of how statins may confer host cellular protection against bacterial infections in the context of airway epithelial cells without the confounding effect from the presence of immune cells. In addition, our discovery could be potentially developed into a host-centric strategy for the adjuvant treatment of pore-forming toxin associated bacterial infections.

Statin-induced immunomodulation alters peripheral invariant natural killer T-cell prevalence in hyperlipidemic patients.

PURPOSE: To assess the difference in the prevalence of invariant Natural Killer T (iNKT) lymphocytes between hyperlipidemic and control individuals and to evaluate changes in iNKT cell levels after 6 months lipid lowering therapy. METHODS: A total of 77 hyperlipidemic individuals (54 ± 5 years) were assigned to simvastatin 40 mg or ezetimibe 10 mg daily for 6 months. Fifty individuals with normal cholesterol levels were used as control. iNKT cells were measured by flow cytometry in peripheral blood. RESULTS: Patients with hypercholesterolemia had significantly lower iNKT cell levels (percentage on the lymphocyte population) compared to control group (0.16 ± 0.04% vs 0.39 ± 0.08%, p = 0.03). iNKT cells significantly increased after 6 months treatment with simvastatin (from 0.15 ± 0.04% to 0.28 ± 0.11%, p = 0.03) but not with ezetimibe (from 0.16 ± 0.05% to 0.17 ± 0.06%, p = 0.55). Simvastatin treatment did not alter the activation status of iNKT cells as measured by HLA-DR expression. Changes of iNKT cells were independent from changes in total (r(2) = 0.009, p = 0.76) or LDL cholesterol (r(2) = 0.008, p = 0.78) reached by simvastatin. CONCLUSIONS: Hyperlipidemic patients have reduced numbers of iNKT in peripheral circulation compared to individuals with normal cholesterol levels. Their number is increasing after long term administration of simvastatin 40 mg but not after ezetimibe.

[Statins and asthma]. / Statyny i astma.

Statins are drugs widely used in the treatment of hyperlipidemia and cardiovascular diseases. They decrease cholesterol synthesis by inhibiting 3-hydroxy-methylglutaryl reductase of coenzyme A (HMG-CoA). It was shown that statins are characterized by a wider spectrum of activity, which was attributed as an extralipid (pleiotropic) one. Although benefits of HMG-CoA reductase inhibitors have been proven in the treatment of cardiovascular diseases, there are attempts to use them in other fields of medicine, such as neurology and rheumatology. At present, anti-inflammatory and immunomodulatory effects of HMG-CoA reductase inhibitors are being particularly examined. Based on the observation mentioned above, the use of statins in allergology has also been attempted. The paper presents selected aspects of statins' effects on immunological reactions and the inflammatory process, pointing to the possibility of statin use in the treatment of asthma.

Atorvastatin attenuates murine anti-glomerular basement membrane glomerulonephritis.

Statins mediate many of their protective effects by lowering lipids as well as by modulating inflammation. Here, we studied their potential immunomodulatory role in renal inflammation using an autoimmune mouse model of anti-glomerular basement membrane glomerulonephritis. Oral treatment with Atorvastatin dramatically reduced albuminuria and histological changes in the kidneys as compared to vehicle-treated control animals. There was a significant decrease in the Th1 and Th17 response in the regional lymph nodes draining the kidneys. This systemic effect was accompanied by decreased infiltration of the kidneys with inflammatory CD4(+) T and Th17 cells, macrophages, and neutrophils in statin-treated mice. Regulatory T cells were not altered in their number, FoxP3 expression, or suppressive capacity, but their interleukin-10 production was significantly increased by statin treatment. Hence, Atorvastatin systemically and locally decreased the Th1 and Th17 response, thereby protecting the mice against anti-glomerular basement membrane glomerulonephritis. Whether statins can be used to treat human autoimmune renal diseases will require more direct studies.

Antiviral effects of statins.

Introducing statins as possible widely-available drugs for the treatment of viral infections requires an in depth review of their antiviral properties. Despite some inconsistency, a large body of literature data from experimental and clinical studies suggest that statins may have a role in the treatment of viral infections due to their immunomodulatory properties as well as their ability to inhibit viral replication. In the present review, the role that statins may play while interacting with the immune system during viral infections and the possible inhibitory effects of statins on different stages of virus cell cycle (i.e., from fusion with host cell membranes to extracellular release) and subsequent virus transmission are described. Specifically, cholesterol-dependent and cholesterol-independent mechanisms of the antiviral effects of statins are reported.

New insights into the pleiotropic effects of statins for stroke prevention.

There is compelling evidence that treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors - "statins" - the most important class of lipid lowering agents, reduces ischemic stroke incidence independent on their effect on serum cholesterol levels. In this review, the non-lipid-mediated - "pleiotropic" - effects of statins as well as their potential implication in developing new treatment strategies for stroke prevention will be discussed.

Effect of HMG-CoA reductase inhibitors on activation of human gammadeltaT cells induced by Mycobacterium tuberculosis antigens.

Lipid rafts are cholesterol-enriched microdomains which act as a platform for the initiation of T-cell activation. To investigate effect of endogenous cholesterol on lipid rafts formation and activation of gammadeltaT cells, human peripheral blood mononuclear cells were stimulated in vitro with Mycobacterium tuberculosis antigens (Mtb-Ag). Lovastatin and fluvastatin, two 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) inhibitors, were used to block endogenous cholesterol biosynthesis. The expression of ganglioside GM1 (GM1), a lipid rafts marker, and CD69, an activation marker, and the level of tyrosine phosphorylation in gammadeltaT cells were measured by flow cytometry. The expression and aggregation of GM1 were also detected with laser confocal microscopy. We found that lovastatin and fluvastatin could obviously inhibit tyrosine phosphorylation and expression of GM1 and CD69 in gammadeltaT cells induced by Mtb-Ag. These results collectively indicated that HMGCR inhibitors might interfere with the formation of lipid rafts and inhibit the activation of gammadeltaT cells induced by Mtb-Ag.

Proposed cut-off for reactivity of anti-HMGCR and anti-SRP antibodies in patients statin-exposed and statin-unexposed.

The therapeutic approach with statins is widely used in the control of dyslipidemias. However, there is no laboratory evaluation to elect patients to make use of this class of therapeutic drugs.We analyzed the prevalence of anti-signal recognition particle (anti-SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies in a heterogeneous cohort of 85 patients in order to determine cutoff reference values for these antibodies.Serum samples from 85 patients were screened for the presence of anti-HMGCR and anti-SRP autoantibodies by enzyme-linked immunosorbent assay. The demographic, clinical, and morphological features were also correlated with anti-HMGCR and anti-SRP antibodies. The patients were divided in 2 groups: A, statin-exposed, and B, statin-unexposed.There was no significant association (P > .05) among anti-HMGCR and anti-SRP titers in relation to age, sex, statin exposure, and CK level. The concentrations of both antibodies were not correlated with symptoms, CK level, or statin exposure. Eleven (12.9%) patients had anti-HMGCR antibodies. We found a tendency (P = .051) toward greater anti-HMGCR positivity in women with no symptoms. Twelve (14.1%) patients had anti-SRP antibodies. There was no sex predominance, and only 1 patient had muscle complaints. Muscular symptoms were present in 31 (36.5%) patients, 4 (12.9%) were positive for anti-HMGCR antibodies, and 1 (3.2%) was positive for anti-SRP antibodies. A total of 54 (63.5%) patients had no muscle symptoms, 7 (13%) were anti-HMGCR positive, and 11 (20.4%) were anti-SRP positive. We found statistical significance for patients with anti-SRP antibodies when asymptomatic and symptomatic patients were compared (P = .029). In contrast, there was no statistically significant difference between symptoms and positivity for anti-HMG antibodies.One of the main aims of this study was to define a cutoff point in a heterogeneous population with different diagnoses. We also demonstrated that anti-HMGCR and anti-SRP antibodies are not 100% specific to immune-mediated necrotizing myopathy. We believe that these antibodies must be tested and interpreted within the specific context.

Immune-mediated necrotizing myopathy due to statins exposure.

Statin-induced necrotizing autoimmune myopathy (IMNM) is an autoimmune disorder induced by anti-3-hydroxy-3-methylglutaryl-coenzyme-A reductase (anti-HMGCR) antibodies. We performed a retrospective clinical, histological, and radiological evaluation of 5 patients with a 3-year therapeutic follow-up. All patients used statins and then experienced proximal weakness that persisted after drug cessation. Muscle biopsies revealed a primary necrotizing myopathy without inflammatory infiltrates. All patients required immunomodulant combination therapy to achieve clinical remission. Magnetic resonance imaging (MRI) showed the presence of edema in the medial gastrocnemius, posterior and central loggia of the thigh, posterior loggia of the arm, and the infraspinatus and subscapularis muscles, as well as extensive inflammation of the subcutaneous tissues and muscolaris fasciae. Serum analysis, muscle biopsy, and MRI are fundamental for IMNM diagnosis and follow-up. The growing use of statins in the general population raises the importance of acquaintance with this disease in clinical practice.

Anti-HMGCR antibody-associated necrotising myopathy and its association with statin use.

A 66-year-old man presented with chest pain and a 1-year history of generalised weakness, accompanied with generalised aches and pains. Symptoms worsened when he was initiated on statins. Investigations yielded high creatine kinase, high HMG-coenzymeA reductase (HMGCR) antibody titre, myopathic features on electromyography and muscle biopsy, and muscle atrophy on MRI. These results were in keeping with anti-HMGCR antibody myopathy. The patient responded well to immunosuppressive therapy.

Clinician-initiated research on treating the host response to pandemic influenza.

To prepare for the next influenza pandemic and other emerging virus diseases, scientists and health officials are focused on developing new vaccines and treatments that target these viruses. Ideally, these interventions could be highly effective, but for many practical reasons these "top down" efforts are unlikely to provide clinicians with what they will need to manage their patients. As a "bottom up" alternative, combinations of generic drugs like statins and angiotensin receptor blockers (ARBs) might be used to treat the host response to infection. These drugs counteract endothelial dysfunction, a central abnormality in these diseases. Observational studies in patients with influenza, pneumonia, sepsis and Ebola suggest they might work. During the 1918 influenza pandemic, children were infected more frequently than adults, but their mortality rate was much lower. Their survival was probably due to better tolerance (reduced pathogen damage), not greater resistance (reduced pathogen burden). The same pattern of susceptibility characterizes other infectious diseases, and it probably reflects the heritage of human evolution. Drugs like statins and ARBs can metabolically reprogram the host response and improve tolerance to infection. Treating the host response is not on the research agendas of international agencies responsible for pandemic preparedness. Consequently, clinicians might have to undertake clinical trials in patients hospitalised with seasonal influenza, pneumonia and sepsis in order to show convincingly whether treating the host response would work. Most candidate generic drugs are inexpensive, widely available, known to be safe and used by clinicians every day. Demonstrating their efficacy would mean that patients in all countries would have access to treatment on the first pandemic or epidemic day.