Inhaled Corticosteroid for COVID: A New Hope?

Hands up who is feeling a bit bruised after the last few weeks of General Practice? It suddenly felt like the flood gates opened further and the demand surged, and I suspect many of us are feeling a bit jaded currently. However, I do feel there is a bit more hope and positive energy in the air more generally at the moment. The sun is out, the bluebells are just starting to peek through in my local woodlands, restrictions are lifting and the vaccination programme continues to roll on. On the back of that, April has seen the publication of evidence supporting the first potential (drug) treatment for COVID in the community - inhaled budesonide. Much like the buses, we have nothing for a year then two pieces of research come out almost simultaneously.

The first was the STOIC trial. This was published formally in the Lancet on the 9th April and was reviewed by Neal in the NB blog earlier in the month when the results came out in pre-print. In summary, inhaled budesonide 800mcg BD, started within 7 days of confirmed COVID in the community, significantly reduced the need for further urgent care review (community, A&E or hospitalisation) with a NNT of only 8. Inhaled budesonide also improved mean time to recovery and the number of days with fever. 

One of the problems with the STOIC trial was the small numbers (146 in total), although the trial was stopped early after an independent statistical review concluded further participants would not alter the outcome or results. Enter the PRINCIPLE trial - a much larger trial which has been recruiting patients with COVID in the community since the beginning of the pandemic and looks at a variety of treatments, one of which is inhaled budesonide, at the same dose as the STOIC trial - 800mcg BD. An interim analysis was posted in pre-print on the 12th of April and was discussed by Neal in his brilliant podcast last week. What were the main findings?

• 2617 patients in total in the community with confirmed COVID, follow up 28 days. 
• Randomised to budesonide 800mcg BD for up to 14 days, usual care or usual care plus other interventions.
• Compared to usual care the budesonide group recovered on average 3 days quicker.
• There was a (currently not statistically significant) trend to a reduced combined end-point of hospitalisation and death from COVID in the budesonide arm. 

The key difference between the STOIC and PRINCIPLE trial was the demographics of the participants. The PRINCIPLE trial recruited people aged ≥65, or ≥50 with co-morbidities, where as STOIC recruited healthier, younger patients with a mean age of ~45. But the results of these trials has led to the Department of Health and Social Care together with the MHRA to recommend that inhaled budesonide 800mcg BD can be considered off-label if ALL of the following apply: 

• Patients with onset of symptoms of COVID-19 within the past 14 days, and symptoms are ongoing. 
• COVID-19 confirmed by PCR test within the past 14 days. 
• 65 years and over OR 50-64 years with a comorbidity consistent with a long-term health condition from the flu list. 

In terms of drug delivery, the options recommended include Pulmicort Turbohaler, Budelin Novolizer and Easyhaler Budesonide. Many of the patients we may consider this treatment in will never have been shown how to use these inhalers, so direct them to the NHS page which has further information about budesonide inhalers, and also to the Asthma UK page which has videos of how to use the various type of inhaler.

So are inhaled corticosteroids (ICS) really a New Hope for primary care treatment of COVID, or are we all getting over excited and ahead of ourselves on the basis of one small trial and an interim analysis in pre-print? Well, I don’t think so and my gut tells me this is likely to be real. I am very much a late-adopter for drugs so this very much goes against my nature, with my inner nerd telling me to put the brakes on and wait for more data, but I think the direction of travel is sound. First, we have large volumes of observational data that patients with respiratory disease on ICS were significantly under represented in hospital admissions with COVID. Second, we have a biologically plausible mechanism as to how ICS may reduce the COVID burden - in vitro studies have shown they reduce replication of SARS-CoV-2 in airway epithelial cells and down regulate expression of ACE2 and TMPRSS2 genes, both of which are critical for viral cell entry. Third, we are now starting to get RCT data supporting this theory. So yes, we need more data to clarify this effect; yes, I think the MHRA are right to be cautious with its recommendations currently; yes, there are questions still to be answered - Will ICS significantly reduce COVID-related hospitalisations and/or death? Will the reduction in time to recovery and fewer days with fever lead to clinically significant improvements, particularly the risk of post-COVID syndrome (for me one of the huge potential benefits)? Well, time will tell, but for the moment I’m certainly feeling that on the COVID front at least, things really are looking a bit more positive.