Rationale for COVID-19 Treatment by Nebulized Interferon-β-1b–Literature Review and Personal Preliminary Experience

Abstract

The inflammatory response to COVID-19 is specifically associated with an impaired type I interferon (IFN) response and complete blockade of IFN-β secretion. Clinically, nebulization of IFN-α-2b has been historically used in China to treat viral pneumonia associated with SARS-CoV. Very recent data show that the use of inhaled type I IFN is associated with decreased mortality in Chinese COVID-19 patients. However, IFN nebulization is currently not standard in Europe and the United States. Therefore, our group has set up a project aimed to evaluate the possibility to nebulize IFN-β-1b (a drug currently used in Europe to treat multiple sclerosis via subcutaneous injections) and to assess the safety of this new mode of administration in SARS-CoV-2 infected patients. We present here literature data that allowed us to build our hypothesis and to develop collaboration between clinical pharmacists, intensivists and nebulization engineers in order to gain first pre-clinical and clinical experience of IFN-β-1b nebulization. After validation of the nebulization method and verification of droplet size compatible with nebulization, the method has been applied to four intensive care patients treated at our university hospital, for whom none of the COVID-19 therapies initially used in France led to significant clinical improvement. All patients exhibited negative viral carriage and experienced clinical improvement 7–16 days after having initiated nebulized IFN-β-1b inhalation therapy. No side effects were observed. All patients were alive within a 90-days follow-up. Although it is not possible to draw firm conclusions on treatment efficacy based on this case report, our study shows that pulmonary IFN-β-1b administration is feasible, with a good safety profile. This procedure, which presents the advantage of directly targeting the lungs and reducing the risks of systemic side effects, may represent a promising therapeutic strategy for the care of patients with severe COVID-19. However, our preliminary observation requires confirmation by randomized controlled trials.

Lung Physiological Variations in COVID-19 Patients and Inhalation Therapy Development for Remodeled Lungs

“…Unfractionated heparin (UFH) has anticoagulant, anti-inflammatory, and antiviral effects; nebulized delivery of UFH to lungs may prevent the entry of SARS-CoV-2 virus into respiratory cells and limit lung injury progression and vascular thrombosis [16]. Similarly, nebulization of IFN-α-2b is being tested in China and France to treat viral COVID-induced pneumonia [17]. The suitability of Hydroxychloroquine (HCQ) as inhalable powders was tested by Albariqi et al [18] using jet-milled techniques.…”

Harnessing Type I IFN Immunity Against SARS-CoV-2 with Early Administration of IFN-β

“… [ 135 ] IFNβ-1b - All treated no France single center inhalation 300 μg (lung delivery 10%) 12 days 4 75 59 (5) HCQ and/or antibiotics & (in some patients: LPV/r & corticosteroids & vitamin C) ICU/severe ARDS (PaO2/FiO2 < 100 mmHg) 33 (22–58) 3 patients improved at day 15 N.R. [ 136 ] IFNβ-1b - All treated no Korea single center N.R. N.R.…”

COVID-19 as a mediator of interferon deficiency and hyperinflammation: Rationale for the use of JAK1/2 inhibitors in combination with interferon

“…5. Nebulized IFN-beta inhalation therapy was associated with decreased mortality in Chinese COVID-19 patients and has also demonstrated safety and efficacy in other studies with a rapid viral clearance in concert with clinical improvement [ 138 , 139 ]. The rationales for using nebulized IFN-beta inhalation therapy have recently been reviewed [ 139 ].…”

“…In addition, it has been used previously in the treatment of HIV-infection [ 174 ]. As addressed above, several studies have been performed or are ongoing, investigating the safety and efficacy of IFN in the treatment of infection with COVID-19, either as monotherapy or in combination with other anti-viral agents [ [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , 139 , [142] , [143] , [144] ]. During the last 30 years, IFN-alpha2 has been used in the treatment of patients with MPNs [ 106 ].…”

“…Regarding the weak type I IFN responses, induced by the the SARS-CoV-2, they have been demonstrated to be associated with longer time to obtain virus clearance and more severe hyperinflammation [ 142 , 143 ]. Therefore, it is intriguing to consider, whether the weak type I IFN responses are compensated by immune mechanisms, which unfortunately then associate with a cytokine storm [ 139 ]. In this context, it might be anticipated that early treatment with IFN may prohibit disease progression by several mechanisms, including both a direct inhibition of virus replication and thereby the virus-promoting IFN-deficiency state but also indirectly by dampening the immune mechanisms that elicit the ensuing hyperinflammation.…”