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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 10  |  Issue : 4  |  Page : 227-232

Biological Therapies and Immunomodulators: Implications in COVID-19


1 Post Graduate, Department of General Medicine, Dr. B. R. Ambedkar Medical College, Bengaluru, Karnataka, India
2 Assistant Professor, Department of General Medicine, Dr. B. R. Ambedkar Medical College, Bengaluru, Karnataka, India
3 Professor, Department of General Medicine, Dr. B. R. Ambedkar Medical College, Bengaluru, Karnataka, India

Date of Submission23-Sep-2021
Date of Decision25-Feb-2022
Date of Acceptance28-Feb-2022
Date of Web Publication25-Oct-2022

Correspondence Address:
Dr. Mohammed Hafeez
Department of General Medicine, Dr. B. R. Ambedkar Medical College, Bengaluru - 560 032, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ajim.ajim_102_21

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  Abstract 


The novel coronavirus disease 2019 is caused by coronavirus and has been seen to cause fatal pneumonia complicated by severe respiratory distress syndrome. Until February 22, 2022, according to the Ministry of Health and Family Welfare, Government of India, there were 181,075 active COVID cases with 4,218,510 discharged patients and 512,344 deaths. As a part of primary prevention, vaccines have been launched, administrated, and under development along with several drugs that are being investigated for treatment and prophylaxis in COVID-19 infection. The World Health Organization conducted SOLIDARITY, a vast scale study and laid down names of potential drugs that can be used in the management of COVID-19 infection including chloroquine (CQ) phosphate, hydroxychloroquine (anti-malarial) Remdesivir, Lopinavir-Ritonavir with or without interferon (anti-HIV), and convalescent plasma therapy. It has also been known that coronavirus has inflammatory pathogenesis which is responsible for the cytokine storm especially in individuals that are susceptible and with coexisting morbidities. This has led to the consideration of anti-inflammatory cytokine drugs including Anakinra and Tocilizumab, the efficacy of which has also been studied in the management of COVID-19 infection. The current evidence of efficacy regarding two particular approaches to the management of COVID-19 are being elaborated in this review article: Immunomodulators and biological therapy. The article critically discusses therapeutic effectiveness and efficacy of immunomodulator drugs for the management of COVID-19 including CQ, 2-deoxy-d-glucose, and biological therapies such as Tocilizumab, zinc, interferon, plasma therapy, and monoclonal antibodies. In addition, immune-altering conditions related to rheumatology and especially tuberculosis has been discussed to a certain need for change in the management of both.

Keywords: Biological therapies, COVID-19 infection, immunomodulators


How to cite this article:
Singh B, Thapashwi B G, Thabsheera H, Mohiddina FK, Shivakumar B R, Hafeez M. Biological Therapies and Immunomodulators: Implications in COVID-19. APIK J Int Med 2022;10:227-32

How to cite this URL:
Singh B, Thapashwi B G, Thabsheera H, Mohiddina FK, Shivakumar B R, Hafeez M. Biological Therapies and Immunomodulators: Implications in COVID-19. APIK J Int Med [serial online] 2022 [cited 2022 Dec 3];10:227-32. Available from: https://www.ajim.in/text.asp?2022/10/4/227/359440




  Introduction Top


The 21st century has introduced the world to a contagious and highly communicable disease, COVID-19, which has been seen to elicit nonspecific symptoms with virulent pathology and become carriers to the population. The World Health Organization declared COVID-19 as an outbreak of Public Health Emergency of International Concern on January 30, 2020, and a pandemic on March 11, 2020.[1] The pathogen identified, coronavirus, is predicated to originate in China (Wuhan wet market in Hubei), also the first country to have witnessed the spread. It has been documented that the virus is genetically analogous to bat coronavirus in the Sarbecovirus, a subgenus. Corona virus has four subtypes: α, β, γ, and δ, in which β subtype has been found responsible for human transmission.[2] The individuals infected with COVID-19 primarily present with respiratory symptoms including cough, fever, breathing difficulty, and olfactory dysfunction complicated by viral pneumonia.[3] The disease is managed with home care, isolation, and minor medical interventions; however, certain people with extended harm, comorbidities, and late diagnosis might require extensive and emergency medical treatment. The high virulence and transmission rate calls for a strategic and systematic approach to screening, diagnosis, and treatment.[4]


  Approaches to Treatment Top


Majority of cases with COVID-19 elicit mild-to-moderate symptoms of upper respiratory infection and have been seen to recover well with home care and isolation alone. The concern lays regarding individuals with complex comorbidities including cardiovascular risk, diabetes, carcinoma, existing pulmonary conditions such as chronic obstructive pulmonary disease, and other forms of chronic illness [Table 1].[5]
Table 1: Summary of immunomodulators prescribed in corona virus disease-2019 infection

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One of the primary drugs that has been seen to be effective and had been used to treat COVID-19 infection in India was chloroquine (CQ). The drug has been globally used as an anti-malarial and acts by increasing endosomal pH which consequently blocks infection.[28] In adjunct, hydroxychloroquine which is comparatively identical to CQ has been used in patients with rheumatic disorders and belongs to the drug class of disease-modifying antirheumatic drugs.[21] The drug is a potent immunomodulator which has been seen to manifest anti-inflammatory properties and prevent organ damage. Similar to CQ, hydroxychloroquine acts by raising the intracellular pH and counteracts the mating process between virus and the endosomes, which ultimately prevents infection.[22]

However, despite its use in India and other countries, the UK Medicines and Health Care Products Regulatory Agency declared that there exists no therapeutic effect of hydroxychloroquine for patients infected with COVID-19 following a large study RECOVERY which was a comparative study to explore mortality in patients treated with hydroxychloroquine and usual care only.[22] The study findings revealed that there was no therapeutic response of hydroxychloroquine in patients with COVID-19 with no reduction in mortality. Hence, post that the utility of hydroxychloroquine in managing COVID-19 has been reduced globally and in India.[8]


  Efficacy of 2-Deoxy-d-Glucose in COVID-19 Infection Top


Very recently, a clinical trial was conducted in India, which consisted of 200–300 patients with moderate-to-severe COVID-19 infection. The clinical trial studied the effectiveness of the drug 2-deoxy-d-glucose in sustaining the viral load, reducing the need for oxygen therapy and length of hospitalization.[23] The mechanics of therapeutic effect of the drug was its accumulation in the infected lung cells which reduced glycolysis and thus, lessened energy production in the infected lung cells. This was seen to reduce the replication of virus and thus, the therapeutic effect.[24]


  Biological Therapies Top


Tocilizumab and baricitinib

The role of neutralizing antibodies fighting COVID-19 infection has come into recognition gradually with their action to enhance capacity immunity in humans at the time of exposure to infection. Tocilizumab is an anti-interleukin 6 receptor which has been seen to demonstrate anti-inflammatory properties to suppress cellular inflammation and extravasation in COVID-19 patients.[25] Tocilizumab has been labeled as an effective and therapeutic treatment in patients infected with coronavirus especially those with severe symptoms.[26] There has been evidence that tocilizumab caused reduction in elevated body temperature and also tapered the intensity of other COVID-19 symptoms. Moreover, on administration of tocilizumab, the oxygen needs in patients reduced by 75%, with betterment in computed tomography findings and pathological results.[27]

The efficacy of tocilizumab was established with a China-based study which led to its approval for treating COVID-19 infection by elevating interleukin-6.[29] It was also observed that patients infected with COVID-19 with disrupted interleukin-6 signaling secondary to the administration of interleukin-6 monoclonal antibody receptor blocker manifesting cytokine storm syndrome, were seen to respond better to tocilizumab.[28] Several studies have demonstrated the implication of interleukin-6 in the severity of COVID-19 infection with great influence on biomarkers including D-Dimer, lactate dehydrogenase, creative reactive protein (CRP), and T cell count. Concluding, tocilizumab being inhibitor to interleukin-6 can be effectively used in the treatment for COVID-19.[29]

According to NIH, for patients on low-flow supplemental oxygen with significantly elevated inflammatory markers and having increased need of oxygen despite treatment with dexamethasone and are within 96 h of hospitalization, tocilizumab and baricitinib can be added to reduce mortality.[30] For the use of baricitinib and tocilizumab, patients must be commenced on glucocorticoids. Tocilizumab should not be given to patients who have received baricitinib and vice versa. There is no availability of data comparing baricitinib and tocilizumab, and the choice depends on availability.[30]

Baricitinib is a janus kinase inhibitor used for the treatment of rheumatoid arthritis. In COVID-19, it is recommended for patients requiring high-flow oxygen or noninvasive ventilation. It can also be used in patients with low-flow oxygen with progressive worsening of clinical condition.[26] It is prescribed for individuals within 96 h of hospitalization or intensive care unit (ICU) level care. When a patient is treated with tocilizumab, baricitinib is used with caution in patients that are immunocompromised.[26]

It has also been documented that individuals treated with tocilizumab with elevated inflammatory markers and pro-inflammatory cytokines have been able to recover by blocking the inflammatory pathway and preventing disease progression. The overall evidence demonstrate reduction in mortality with tocilizumab.[26] The results came from a meta-analysis of 27 randomized controlled trials comprising of more than 10,000 patients hospitalized due to COVID-19 infection. The all-cause mortality was found to be lower in individuals receiving tocilizumab in comparison to placebo or standardized care.[30] In an open-label trial in the UK comprising 4116 people with suspected or confirmed COVID-19 infection with hypoxaemia (SpO2 <92% on room air) and CRP level greater than 75 mg/L. The addition of 1 to 2 doses of tocilizumab in combination to usual care reduced the 28-day mortality rate.[31]

Similarly, another open-label, international randomized trial comprising 803 patients with severe COVID-19 infection but admitted to ICU and required respiratory and cardiovascular support. The study findings revealed reduction in mortality using interleukin-6 (IL-6) pathway inhibitors including tocilizumab and sarilumab. Both of them were seen to reduce in-hospital mortality in comparison to the provision of standard care.[32]

Zinc

Zinc has always been known for its implication in immune function and is important for the production of antibodies and white blood cells.[33] Zinc has been seen to enhance concentrations of pro-inflammatory cytokines including IL-1, 6, and tumor necrosis factor alpha. Zinc supplementation in COVID patients was to enhance the production of polymorphonuclear cells to combat infection.[34] The function of zinc in managing COVID-19 can be explained by the fact that, elevated intracellular zinc causes interference with proteolytic mechanisms concerning polyproteins in several RNA strains especially coronavirus.

Interferon

Interferons are structural and functional cytokines which act as communicators between the antigen and the cell and exhibit a significant role in immune system modulation. The function of interneurons is to activate the natural killer cells alongside macrophages. The three types of interferons which have been seen to be effective in curbing viral infections are interferon (IFN) I, II, and III with sub-types IFN-α, β, and γ.[35] The subtype 1 interferon is known to cause activation of intracellular defense against pathogen and strengthens the process of innate immunity and adaptive immunity development. A study finding demonstrated that patients with mild-to-moderate symptoms treated with interferons in combination with moxifloxacin and lopinavir had better outcomes. Additionally, adding methylprednisolone to the triad reduced the length of stay of ICU patients and also led to early discharge from hospital.[46]

It is a well-documented fact that combination of signal transducer and activation of transcription 1 (the key protein) forms the basis of interferon-related immune response. This response is antagonized by the coronavirus which points to hiked response limit of immune cells to interferons when COVID infections occur.[37] However, in India, the utility of interferons led to a diffuse response in COVID treatment which also highlighted significant mortality. The rates were higher amongst elderly patients due to existing enhanced inception of interferon-initiated immune reactions. This also explains the reason behind the less infection rate in children due to premature interferon induction and inadequately developed immune system.[38]

Furthermore, interferons are not just a treatment modality in COVID-19 patients but are also a means to diagnose the stage of infection of COVID-19 in humans. For instance, the extent of viral invasion and consequent interferon (type 1) reactions are important in understanding the severity of infection in humans.[38] The studies have been done to study and imply the association between viral load and severity of infection in COVID-19 which also led to differentiation of pathogenesis from previously existing SARS-CoV in India.[38]

Plasma therapy

The administration of immunoglobulins or convalescent plasma therapy can be initiated in combination with methylprednisolone for critically ill patients. The administration of plasma therapy has seen to reduce length of stay at hospital and mortality in critical patients.[39] Convalescent plasma therapy, also known as passive immunity therapy, has been used widely for the management of viral infections such as H1 N1, Ebola, and SARS-CoV-1. The conveyed benefits include improvement in clinical outcomes, reducing disease severity duration of hospitalization, and mortality in patients with COVID-19; however, the outcome depends on the concentration of antibodies in the plasma causing utilization of the virus.

ICMR conducted an open-label phase II multicenter randomized controlled trial in 39 public and private hospitals concerning the use of convalescent plasma therapy in the management of patients with moderate COVID-19 infections in India (PLACID trial). The study concluded that convalescent plasma therapy did not cause reduction in progression to severe levels nor it improved the overall mortality in the group receiving the same in comparison to the group with placebo.[40] PLACID is the world's largest trial concerning convalescent plasma therapy with 464 participants having moderate COVID-19 infection. Similar studies were conducted in China and the Netherlands which demonstrated no improvement in the clinical outcomes of hospitalized COVID-19 patients.[40]

ICMR advised no indiscriminate use of convalescent plasma therapy in the management of COVID infection. However, it can be used for individuals in the early stage of COVID-19 disease, from 3 to 7 days of onset of symptoms but no later than 10 days. The potential recipient should not have IgG antibodies against the COVID-19 and an informed consent must be taken.[40]

Monoclonal antibodies

Along with active antibody therapy like plasma infusion, passive antibody administration is also a therapeutic means to manage COVID-19 infection. This implication can be understood by the fact that passive antibodies have the ability to distinguish regions of epitope on the virus which can genuinely reduce disease severity and the virus replication rate.[41] Indian practitioners and medical professionals around the globe resorted to the use of monoclonal antibody due to the understanding of genesis of COVID-19 infection. It is recognized that COVID infections initiates with complex interaction of receptor binder with S protein and angiotensin-converting enzyme (ACE-2) located on target receptor. Thus, the monoclonal antibodies when administered bind to ACE-2 and inhibit the entry of the virus into the cell.[42]

However, the existing literature implies that monoclonal antibodies have the ability to identify a single epitope and thus, will require to partial therapeutic effect against the COVID antigen.[43] Another challenge that monoclonal antibody administration encounters is that it requires time to have adequate level in blood, which is difficult to be achieved in patients which require immediate intervention.[10]

The monoclonal antibody cocktail therapy gained recognition and popularity by the former US President Donald Trump from 2020 in the management of COVID-19.[44] Although the antibody cocktail promises to reduce the severity of COVID-19 disease in high-risk patients with comorbidities, yet it cannot be recommended for everyone especially for those infected with omicron variant. A single dose of the cocktail therapy casirivimab plus imdevimab (REGEN-COV) is available in India and omicron variants are shown to evade this antibody cocktail.[44] Sotrovimab is a human neutralizing monoclonal antibody which is still effective against omicron but not available in India.[45] It was reported that, an infected patient it does not improve in 5 days and continues to experience significant symptoms, and then monoclonal antibody therapy can be considered.[46]

The efficacy of monoclonal antibody administration is it stake due to newer variants infecting the population. The efficacy of monoclonal antibody cocktail therapy yet needs to be discovered in relevance to omicron and other virus strains.[46] A latest study from Columbia University in the US conducted in collaboration with the University of Hong Kong concluded that omicron invades the passive protection received from vaccination and natural infection and can render the most monoclonal antibody therapies ineffective.[46]

Future therapies

Several international and Indian studies are in progress to establish evidence for plasma therapy in managing patients with COVID-19 infection. Several vaccines are being tried and tested, which enables the worldwide immunity to COVID-19. Certain biological therapies such as Ig fused with ACE2 cell culture or nonspecific protease inhibitor like camostat mesylate are being tested to inhibit infection and disease suing pseudo-virus which bears the identical S protein as that of SARS-CoV-2.[47]


  Conclusion Top


It is evident that no particular therapy, immunomodulators, or biological therapy has been concretely added to the management protocol of COVID-19 infection. However, the above-mentioned evidence does quote and emphasizes the therapeutic efficacy of different drugs demonstrating immunomodulating action. Additionally, biological therapies such as plasma therapy and interferons are somewhat in the stage of conflict with medical professionals in India and around the globe for its efficacy in managing COVID-19 infection. Thus, to sum up a two-pronged holistic approach based on the doctor's clinical acumen and available resources and the suitability of the patient's need and pocket, must be considered to formulate a strategy for a particular patient.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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