As the world struggles to overcome the current COVID-19 pandemic with non-pharmacological interventions, in the absence of an effective drug or vaccine, existing immunomodulators are being repurposed. A new study published on the preprint server medRxiv* in May 2020 shows no clinical benefit to the use of one such drug, called interferon beta 1b (IFN beta1b).
Why Study IFN beta1b in COVID-19?
The clinical course of COVID-19 is varied. In the vast majority of people, it is asymptomatic or mild, but in a small percentage, it becomes symptomatically severe. Such patients typically develop pneumonia, and acute respiratory distress syndrome (ARDS), and about half of them die.
The lack of a specific drug in the presence of significant mortality prompted the current study. The molecule IFN beta1b showed potent in vitro inhibition of SARS-CoV and MERS-CoV. In one such study, it also inhibited the current SARS-CoV-2 virus more powerfully than it did SARS-CoV. Thus, some guidelines advise the use of subcutaneous IFN beta1b along with other antivirals.
On the other hand, in the absence of sufficient clinical evidence gathered from randomized controlled trials, it is difficult to come to a conclusion about the use of this drug. The current study is thus focused on the efficiency of IFN beta1b in COVID-19, concerning in-hospital mortality in patients who took it or did not.
Novel Coronavirus SARS-CoV-2 Colorized scanning electron micrograph of an apoptotic cell (green) heavily infected with SARS-COV-2 virus particles (purple), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
The Infection-Inflammation-Injury Pathway
The SARS-CoV-2 binds to the ACE2 receptor on the type II alveolar cells in the lungs. The ACE2 receptor is also an enzyme of the category known as exopeptidases.
As the virus invades host cells, the inflammatory and immune response is activated, including the pathway called JAK-STAT. This results in the synthesis of type 1 IFNs, which restrict the spread of the virus and modulate immunity via macrophage, NK cells, and T as well as B cells. When the production of IFNs is blocked, virus survival is enhanced.
However, it is also thought by some that COVID-19 initiates a hyperactive immune response, which worsens the virus-induced lung injury, leading to ARDS and a poor clinical prognosis. Despite the overactive immune cascade, the virus continues to proliferate and spread.
The elevated levels of cytokines and chemokines, which are cellular signaling molecules, also activates the coagulation system and damage the microvascular bed, leading to thrombi within the smallest blood vessels. Fibrinolysis is inhibited as well, which can trigger coagulopathy as a result of sepsis, or disseminated intravascular coagulation, culminating in extensive microcirculatory disruption and multi-organ failure.
Initially, there was a wave of interest in repurposing antivirals against COVID-19. The current recommendations about therapy focus on immunomodulation, including IL-6 inhibitors like tocilizumab, or broad-spectrum immunomodulatory drugs like hydroxychloroquine and glucocorticoids.
Immunomodulation by Interferons
Earlier evidence from therapies used in SARS or MERS suggests interferons could play the key role. These molecules have antiviral effects, as shown by their effect on illnesses like HCV because they activate an RNA-ase enzyme that degrades the viral nucleic acid strand. IFNs also inhibits RNA translation, block the packaging of the virus within its capsid and viral particle release from the infected host cell.
In vitro studies show IFN activity against MERS, confirmed by animal studies, but clinical evidence is lacking. The current study is aimed at evaluating the efficacy and safety of IFN beta1b in treating COVID-19 pneumonia.
The Role of IFN beta1b
The study was carried out in a retrospective cohort design and included all adults hospitalized between February 23 and April 4, 2020. Patients with moderate to severe pneumonia were given IFN beta1b. The study endpoint was in-hospital mortality.
The study included all adults (aged 16 years or more) hospitalized with COVID-19 at one Madrid hospital, who achieved recovery or died between February 23 and April 4, 2020. Both confirmed and probable COVID-19 cases were included.
Demographic details, medical history, COVID-19-specific treatment history, the clinical condition at admission, and laboratory test parameters on admission were collected from electronic health records. Patients with moderate and severe disease were classified based on their fraction of inspired oxygen and the need for supplementary oxygen or mechanical ventilation.
Patients with moderate to severe pneumonia received 3-5 doses of IFN beta1b subcutaneously. Other drugs were also used, including hydroxychloroquine, chloroquine, lopinavir and ritonavir, anti-inflammatory drugs, and glucocorticoids.
Of 256 patients in the study, about 60% were male, and the average age was 64 years. About 45% had hypertension, while many also had diabetes and heart disease. About 61% had two or more underlying medical conditions.
About 54% had moderate to severe COVID-19. Among the discharged patients, 90% were diagnosed with pneumonia. About 77% received hydroxychloroquine, 63% azithromycin, and 41% IFN beta1b.
Did IFN beta1b Produce Clinical Benefit?
Fewer patients who received IFN beta1b had two or more medical conditions other than COVID-19, compared to those who did not (35% vs. 43%). This is explained by the fact that due to a shortage of the drug, those with higher life expectancy before admission were selected for this therapy.
Those who received IFN beta1b were more likely also to receive hydroxychloroquine and lopinavir/ritonavir.
The overall mortality rate was about 25% or 63 patients of 256 overall. Just over a fifth of the 106 patients who received IFN beta1b died, compared to 27% of those not on the drug.
The in-hospital mortality in patients who did not receive IFN beta1b was insignificantly higher than in the other group. However, since many patients in both groups were treated with a variety of potentially effective drugs, it is challenging to ascribe efficacy to any one drug. A survival benefit was found with hydroxychloroquine; however, this needs to be confirmed.
Multivariate analysis showed that the leading indicators of mortality are older age over 65 years, clinical severity at the time of admission, and not being treated with hydroxychloroquine. Interferon treatment did not show any link with an increase in survival.
The timing of IFN administration in viral infection has been shown to be crucial to the success or harmfulness of the therapy in mouse models, where early therapy healed. Still, late therapy worsened inflammation triggered by viral infection. In the current study, this could not be replicated as the median delay from onset of symptoms to admission was seven days.
An ongoing trial is attempting to assess the value of a combination of lopinavir/ritonavir and IFN beta1b in MERS, but the current study did not find any survival benefit. This is the first study to evaluate the effectiveness of IFN beta1b in SARS-CoV-2, but it failed to find significant benefit. More work may be required to elicit any potential efficacy when given at the early stages of disease in controlled trials using larger patient samples.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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