Immunomodulators and SARS-CoV-2: Management of the Dysregulated Immune Response

1. Senior Resident, Department of Pulmonary Medicine, KS Hegde Medical Academy, Mangalore, Karnataka, India. 2. Professor, Department of Pulmonary Medicine, KS Hegde Medical Academy, Mangalore, Karnataka, India. 3. Associate Professor, Department of Pulmonary Medicine, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India.

Abstract

The Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) resulted in millions of deaths worldwide. In adults, it can lead to serious complications such as Acute Respiratory Distress Syndrome (ARDS), renal failure, encephalitis, acute cardiac illness, thromboembolism, and multiorgan failure. However, in infants and children, it causes mild illness. The current evidence showed hyperinflammatory syndrome is the reason for most of the deaths in patients with severe COVID-19. There are increasing research activities around immunomodulatory drugs to manage SARS-CoV-2 induced dysregulated immune response. However, these immunomodulatory drugs are currently approved by FDA for the prevention and treatment of certain inflammatory disorders, such as rheumatoid arthritis, gout, recurrent pericarditis, and multiple sclerosis. Here, we summarise the drugs studied in several randomised clinical trials to demonstrate the efficacy and safety in treating the uncontrolled immune response of COVID-19 patients.

Cytokine storm, Hyperinflammation, Randomised clinical trial, Severe acute respiratory syndrome coronavirus-2

The Coronavirus Disease (COVID-19) pandemic has resulted in 6.6 million deaths globally (1). Genetic variation or polymorphism within the human population appears to be the determinant factor for susceptibility to infection, host immune response, and fatality to the evolving Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants and subvariants. COVID-19 follows a destructive inflammatory response with the release of abundant proinflammatory cytokines, including IL-6, Interferon-α (IFN-α), Tumour Necrosis Factor (TNF), and more in a situation known as a “cytokine storm.” Cytokines are associated with Disseminated Intravascular Coagulation (DIC), vascular leak, activation of the complement and coagulation cascade, acute phase protein production, lung injury, and cardiomyopathy. The cytokine storm eventually leads to Acute Respiratory Distress Syndrome (ARDS), multiorgan failure, and unfavourable prognosis (2). The dysregulated immune response plays a key role in the clinical deterioration of COVID-19 patients. Here, we review the latest evidence-based practices on the usage of drugs that regulate the hazardous immune response in the management of COVID-19.

Hydroxychloroquine (HCQ) and Chloroquine

It was the most suggested drug for postexposure prophylaxis and treatment of COVID-19 at the beginning of the pandemic, given evidence of in-vitro inhibition of SARS-CoV-2 and inhibition of Major Histocompatibility Complex (MHC) class II expression, antigen presentation, and immune activation via Toll-like receptor signalling and IFN gene stimulation by cyclic GMP-AMP Synthase (cGAS) (3). Thus, it can decrease the production of the proinflammatory cytokines implicated in a cytokine storm. The Solidarity Trial, RECOVERY Trial (UK), ORCHID Trial, and other Randomised Controlled Trials (RCTs) showed that HCQ does not have mortality benefits in hospitalised patients with COVID-19 compared to Standard of Care (SOC) (4),(5),(6),(7).

The potential toxicity of HCQ includes QTc prolongation, arrhythmias, and neuromyotoxicity. HCQ may increase the risk of nausea, vomiting, abdominal pain, drowsiness, and headache in patients with COVID-19. However, HCQ is considered safe for treating patients with autoimmune diseases or malaria (8).

Colchicine

It is one of the oldest anti-inflammatory drugs. Only oral formulations are currently approved by FDA for the prevention and treatment of gout and familial mediterranean fever (9),(10). Colchicine is also used in various conditions (off-label), including Behcet syndrome, recurrent pericarditis, calcium pyrophosphate crystal arthritis (pseudogout), postpericardiotomy syndrome, and secondary prevention atherosclerotic cardiovascular events, Sweet syndrome, cutaneous small-vessel vasculitis. Colchicine inhibits microtubule polymerisation, inflammasome activation, neutrophil chemotaxis, and the release of Interleukin-1 (IL-1) beta (11),(12),(13),(14).

Colchicine for Community-treated COVID-19 patients (COLCORONA), a placebo-controlled, RCT involving 4,488 non hospitalised patients, showed that the colchicine arm failed to reach its primary outcome of reducing hospitalisation and death with increased gastrointestinal side-effects compared to the placebo arm (15). In Randomised Evaluation of COVID-19 Therapy (RECOVERY) Trial it was observed that there was no noticeable difference in the 28-day mortality between colchicine and placebo groups (16). However, a prospective, randomised Greek Study of Colchicine effects on COVID-19 complications (GRECCO-19), involving 105 hospitalised patients, demonstrated a significant decrease in the primary clinical outcome of a two-point deterioration on a seven-point clinical status scale (17).

The minor adverse events of colchicine are nausea, vomiting, abdominal bloating, diarrhoea, loss of appetite, and the major adverse events include neuromyotoxicity and blood dyscrasias (18),(19).

Fluvoxamine

It is a Selective Serotonin Reuptake Inhibitor (SSRI) with a high affinity for the sigma-1 receptor in immune cells, resulting in a reduced inflammatory response during sepsis and decreased shock in murine sepsis models. An in-vitro study showed that fluvoxamine brought down the inflammatory gene expression in human endothelial cells and macrophages (20). In a randomised, placebo-controlled clinical trial involving 152 non hospitalised symptomatic COVID-19 patients, there was no clinical deterioration in patients treated with fluvoxamine compared to six (8.3%) patients in the placebo arm over 15 days (21). In a prospective, non randomised, observational study involving 113 non hospitalised patients with COVID-19, there was no hospitalisation in the fluvoxamine group, compared to six patients in the observation group who were treated without fluvoxamine, including Intensive Care Unit (ICU) treatment for two patients (22).

Corticosteroids

In a multicentre, randomised, open-label trial of dexamethasone (RECOVERY trial), it was noted that 6 mg of dexamethasone daily for 10 days in patients who were on either oxygen alone or invasive mechanical ventilation, showed a reduction in the 28-day mortality but the survival benefit was not observed in patients who were not on oxygen support (23). In a phase II b, randomised, placebo-controlled trial (Metcovid), methylprednisolone was given to hospitalised patients with COVID-19 as adjunctive therapy, which showed no mortality benefits at 28 days in both methylprednisolone and placebo arms. However, in subgroup analysis, low mortality rate was observed at day 28 among patients aged above 60 years in the methylprednisolone arm (24). The Randomised, Embedded, Multifactorial Adaptive Platform trial for Community Acquired Pneumonia (REMAP-CAP) studied the effect of hydrocortisone in patients with severe COVID-19 and showed no significant benefit in both groups including hydrocortisone given at a fixed dose and the shock-dependent hydrocortisone (25).

The National Institutes of Health (NIH) treatment guideline for COVID-19 recommends dexamethasone along with remdesivir for hospitalised patients who require supplemental oxygen or dexamethasone alone when remdesivir is not available or contraindicated. There is no recommendation for the use of glucocorticoids in hospitalised COVID-19 patients who are not on oxygen therapy. The glucocorticoids that can replace dexamethasone are methylprednisolone, prednisone, and hydrocortisone at a dose of 32 mg, 40 mg, and 160 mg, respectively equivalent to 6 mg of dexamethasone (26).

Interferons (IFNs)

The IFNs are proteins produced by various cells in response to infections. They have antiviral, antitumour, and immunomodulatory effects. IFNs therapeutic use is already known and currently used in treating multiple sclerosis. It has been reported that IFNs inhibit SARS-CoV-2 replication in-vitro, mainly IFN-beta (27).

A randomised, phase II clinical trial involving hospitalised patients with COVID-19 treated with a three-drug combination including IFN beta-1b, ribavirin, and ritonavir/lopinavir showed substantially shorter median time from the initiation of triple therapy to negative nasopharyngeal swab in the combination group than in the control group (28). In an open-label, RCT, IFN beta-1a was studied in hospitalised COVID-19 patients, and it demonstrated that there was no noticeable benefit observed in the primary outcome of time to clinical response and length of hospital stay, including ICU stay (29). A phase II, randomised clinical trial of Pegylated IFN alfa-2b (PEG-IFN alfa-2b) in hospitalised patients with moderate COVID-19, showed considerable improvement in clinical condition on day 15 in the PEG IFN alfa-2b group (n=20) than the control group (n=20) (30).

Interleukin-1 (IL-1) Inhibitors

The IL-1 is a potent proinflammatory cytokine. Anakinra is a recombinant human IL-1 receptor inhibitor. FDA has approved it for patients with moderate to severe rheumatoid arthritis, cryopyrin-associated periodic syndromes, gout flares, and idiopathic recurrent pericarditis resistant to colchicine (31),(32),(33).

A RCT was conducted on hospitalised patients with mild to moderate COVID-19 pneumonia (CORIMUNO-ANA-1) to study the efficacy of anakinra. The study showed that anakinra had no significant benefit in improving the clinical outcomes of these patients (34). In a retrospective cohort study, the use of high-dose anakinra in patients with severe COVID-19, showed clinical improvement in 72% of patients treated with high-dose anakinra than the control group (35). In a cohort study of anakinra for severe COVID-19, it 2reduced the necessity of invasive mechanical ventilation and also lowered the mortality without serious adverse events (36).

The NIH treatment guideline for COVID-19 does not recommend IL-1 inhibitors for treating hospitalised COVID-19 patients as there is no sufficient evidence (37).

Interleukin-6 (IL-6) Inhibitors

The IL-6 is one of the prime inflammatory mediators in COVID-19, produced by macrophages, lymphocytes, and fibroblasts. The agents that block the IL-6 pathway include IL-6 receptor antagonists such as tocilizumab, sarilumab and direct IL-6 inhibitors (siltuximab). Currently, FDA has approved tocilizumab for treating patients with rheumatic diseases and cytokine release syndrome, sarilumab for patients with rheumatoid arthritis, and siltuximab for patients with multicentric Castleman disease (38),(39),(40).

In the REMAP-CAP study, hospitalised patients with severe COVID-19 who were treated with IL-6 receptor antagonists showed survival benefits (41). In an open-label, randomised, platform trial that included hospitalised COVID-19 patients (RECOVERY), tocilizumab improved survival and other clinical outcomes (42). In addition to that, a randomised, double-blind, placebo-controlled trial, including hospitalised COVID-19 patients (EMPACTA), showed reduced probability of progression in the clinical status that necessitates the use of mechanical ventilation, but failed to improve survival in the tocilizumab group (43).

The NIH COVID-19 treatment guidelines panel recommends tocilizumab or sarilumab along with dexamethasone in recently hospitalised patients within three days of admission who require ICU care, including High-Flow Nasal Oxygen (HFNO), Non Invasive mechanical Ventilation (NIV), or invasive mechanical ventilation, and who are not admitted to ICU but had rapidly increased oxygen needs, significantly increased inflammatory markers (CRP ≥75 mg/L), and required HFNO or NIV. The panel does not recommend siltuximab for treating severe COVID-19 disease, except in clinical trials (44).

Janus Kinase (JAKs) Inhibitors

The JAKs are cytoplasmic tyrosine kinases that mediate and augment extracellular signals from cytokines via the JAK-STAT pathway. It has four members in the family such as JAK 1, JAK 2, JAK 3, and tyrosine kinase 2 (TYK2). Inhibitors of Janus-kinases hinder the Signal Transducer and Activator of Transcription (STAT) protein activation. JAK inhibitors are effective in treating patients with inflammatory diseases (45). Among JAK inhibitors, baricitinib has antiviral activity theoretically in addition to immunomodulatory effects (46). Adverse effects of JAK inhibitors include infection, reactivation of herpes viruses, venous thromboembolism, myelosuppression, and gastrointestinal perforation (47),(48),(49).

In a double-blind, placebo-controlled, RCT, the combination therapy of baricitinib and remdesivir in hospitalised COVID-19 patients had reduced recovery time and accelerated the clinical recovery, notably among those receiving High-Flow Nasal Cannula (HFNC) or NIV compared to placebo plus remdesivir (50). In a multinational, placebo-controlled, randomised trial of baricitinib plus SOC in hospitalised COVID-19 adults who were not on invasive ventilation (COV-BARRIER study), baricitinib with SOC significantly reduced 28-day mortality (51). A prospective cohort study, conducted on 238 hospitalised COVID-19 patients to correlate the clinical outcome of baricitinib at a high dose with its usual dose, showed reduced requirement of critical care support and rehospitalisation with mortality, compared to those with mortality to its usual dose (52).

In another placebo-controlled, RCT, tofacitinib was studied in patients who were hospitalised for COVID-19 pneumonia, showing that the studied drug reduced the composite outcome of respiratory failure and death at 28 days compared with the placebo (53). A multicentre, single-blind, RCT of ruxolitinib in treating severe COVID-19, showed statistically insignificant clinical outcomes (54).

The NIH treatment guideline for COVID-19, recommends baricitinib or tofacitinib along with dexamethasone, and remdesivir in recently hospitalised patients who require HFNC or NIV. The other JAK inhibitors are not recommended, except in clinical trials (55).

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Inhibitors

The GM-CSF is a haematopoietic growth factor and proinflammatory cytokine that plays an important role in immune-mediated diseases. It is produced by various cells including macrophages, endothelial cells, fibroblasts, neutrophils, eosinophils, T-cells, mast cells, and Natural Killer (NK) cells. GM-CSF-derived signals regulate macrophage number and function, including alveolar macrophages (56). Increased GM-CSF levels have been reported in patients with COVID-19, and inhibition of GM-CSF signals by anti-GM-CSF monoclonal antibodies may help reduce the hazardous immune response. The direct GM-CSF inhibitors include lenzilumab, gimsilumab, namilumab, and otilimab. GM-CSF receptor inhibitor includes mavrilimumab, which targets its alpha subunit (57),(58).

In a phase II, placebo-controlled, RCT, involving patients hospitalised for severe COVID-19 pneumonia were treated with otilimab (OSCAR trial), didn’t show any significant outcomes in the otilimab group compared to the placebo group (59). In a randomised, phase III, placebo-controlled trial, lenzilumab efficacy and safety were studied in recently hospitalised COVID-19 patients (LIVE-AIR trial). Lenzilumab showed significant ventilator-free survival benefits in hypoxaemic patients who were not on mechanical ventilation (60). In a multicentre, randomised, placebo-controlled trial, mavrilimumab was studied in patients who were hospitalised for severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID). There were no significant clinical outcomes in the mavrilimumab arm compared to the placebo arm (61).

The NIH COVID-19 guidelines panel does not recommend GM-CSF inhibitors for the management of COVID-19 as there are no sufficient data (62).

Intravenous Immunoglobulins (IVIG): Non SARS-CoV-2 Specific

In a multicentre, retrospective cohort study, the clinical efficacy of IVIG was analysed in patients hospitalised for severe COVID-19 pneumonia (63). The interpretation of the study results was hard as there was no randomisation of patients to receive either IVIG or SOC without IVIG, and both groups were treated with concomitant therapies for COVID-19.

Investigational Immunotherapy Drugs

Vilobelimab is an antihuman complement factor 5a monoclonal antibody. It was studied in phase III, multicentre, double-blind, placebo-controlled, RCT involving critically ill patients with COVID-19 on invasive mechanical ventilation (PANAMO trial), and showed a consistent decrease in 28-day all-cause mortality in vilobelimab arm compared to the placebo arm (64).

Peg IFN lambda, a type 3 IFN, has innate antiviral properties with activity against respiratory pathogens. In a double-blind, placebo-controlled, RCT involving 60 non hospitalised patients with COVID-19, on day 7, 24/30 (80%) patients had an undetectable viral load in the peg IFN lambda group compared to 19/30 (63%) patients in the placebo group (p=0·15). Hence, it has the potential to shorten the duration of viral shedding and prevent clinical deterioration (65).

In a phase II, double-blind, placebo-controlled, RCT, inhaled nebulised IFN beta-1a (SNG001) was studied in 101 patients with COVID-19. On day 15 or 16, patients treated with SNG001 showed a greater clinical improvement on the WHO Ordinal Scale for Clinical Improvement (OSCI) than the placebo group (66).

Bucillamine is an oral antirheumatic drug. Currently, a multicentre, randomised, phase III trial of bucillamine for outpatients with mild-to-moderate COVID-19 is going on; results are awaited (67). The other immunotherapy drugs under investigation include Mesenchymal Stem Cell (MSC) therapy, NK cells, and more (68),(69).

A brief description of selected clinical data on immunomodulators in COVID-19 is presented in (Table/Fig 1) (4),(15),(16),(17),(21),(22),(23),(24),(25),(28),(29),(30),(34),(36),(41),(42),(43),(50),(51),(53),(59),(60),(61).

Conclusion

Glucocorticoids, JAK inhibitors such as baricitinib or tofacitinib, and IL-6 inhibitors like tocilizumab or sarilumab suppress the hazardous immune response and improve the clinical outcome of COVID-19 patients when used judiciously. However, other agents need to be studied in larger, well-designed studies for their effectiveness.

DOI and Others

DOI: 10.7860/JCDR/2023/60636.17733

Date of Submission: Oct 11, 2022
Date of Peer Review: Nov 21, 2022
Date of Acceptance: Dec 30, 2022
Date of Publishing: Apr 01, 2023

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? No
• Was informed consent obtained from the subjects involved in the study? No
• For any images presented appropriate consent has been obtained from the subjects. No

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