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A round up on COVID-19 and the Digestive System.

When COVID-19 appeared on the scene a lot of strange, interesting, and terrible things happened in the world. Of particular interest to me was how many companies in the MedTech space pivoted their technology to meet some aspect of the pandemic. As one of the most niche companies out there, we at Motilent kept our heads down and focused on not going out of business as everything shut down around us.As a friend said at the time: “Until Covid starts presenting with GI symptoms there’s not much we can do” (The friend said it less diplomatically but I’ll leave that to your imagination!) 

 

 

The months and now years rolled on and many companies in our space now have a new respiratory side-gig but, being ever late to the party, I thought now was a good time to flick through the literature and see what, if anything was going on with digestive disease. Could we now (a year later) roll up our sleeves and get stuck in? 

 

Here’s what I found on pubmed (via Twitter). I do not claim this is comprehensive.

 

1) Biological mechanisms of COVID-19. It was news to me when I read about it but apparently there’s a receptor called ACE2 that plays a role in intestinal homeostasis and is found along the GI tract. The SARS-CoV-2 virus binds directly to this receptor to enter the cell meaning that the GI tract can serve as an infection site for the virus. Potentially, people with underlying GI disease especially with leaky gut or influence low-grade inflammation along the gut potentially increasing susceptibility to infection by this route. Already, we’re getting into a place that is not that well characterised in the literature compounded by my relative ignorance around mucosal immunology but suffice to say, there seems to be a ‘back door’ for infection in our GI tract through this receptor. More can be read here.

2) Digestive symptoms and COVID-19. This is a more complex topic and there’s been a couple of nice little articles out that point towards the post-viral implications of COVID-19 on the GI tract.

 

Cooney et al. examined acute chronic GI symptoms post COVID infection over a 6 month follow up period in 48 patients using a web-survey. They found that at 6 months 43.8% reported new GI symptoms (83.3% reported no GI symptoms before COVID) and led to them asking if this could be a new type of post-COVID-19 IBS. The main symptoms reported were pain (29.2%) and diarrhoea (19%). The authors acknowledge the usual weaknesses of such studies (self-reported symptoms, uptake bias, small numbers etc) but the presence of post-infective, new GI symptoms is interesting and this study may well power future investigations.

 

A case study by Courtney et al. walks us through an episode of post-viral gastroparesis in a 16-year old who underwent scintigraphy and was found to have delayed gastric emptying. This was resolved with a spot of decompression and erythromycin to get things moving again which led to the situation improving. While it’s difficult to take a lot away from case studies, it did produce some nice images (which I’m all about) and plants a flag for those seeing evidence of gastroparesis in COVID patients. To the group which published the work: can you please do a cine MR next time so we can see those contractions?  Looking at the stills, I’d bet this subject was hyper-contractile with a difficult pylorus.

 

 

Oshima et al. found that people with functional dyspepsia and IBS  experienced worsening symptoms  likely as a result of the stress caused  by the pandemic.  Although these findings are perhaps not super unexpected (and I see very few areas where our particular approach to digestive disease can particularly help), they serve as a reminder that when life’s stresses weigh on us mentally, their impacts can be manifested physically through our digestive system. In fact,  I’m surprised with all the uncertainty over the last few years that a lot more people have not yet shown up with IBS (or maybe they’re out there, but undiagnosed due to being fairly low down on most hospitals’ priorities right now).

 

So in summary, Motilent’s not about to pivot its business. GI complaints remain a constant – but largely de-prioritised – side effect of the general distress caused by the pandemic, and there are some interesting biochemical mechanisms related to GI and Covid to explore. But Motilent  will remain focused on helping healthcare systems play catchup with all the missed appointments over the last several years, using time and cost-saving innovations borne from deep understanding of our clinical vertical.

Are we treating to the right target?

Nothing makes more sense than the ‘treat to target concept’ in IBD. Every patient is different, IBD is complex, keeping a close eye on response is central to the precision medicine paradigm and min-maxing healthcare resource. 

This is why the recent STARDUST study published in Lancet Gastro may have left a few people disappointed where it concluded that timely escalation of ustekinumab therapy for patients with Crohn’s disease, based on early endoscopic response, clinical symptoms, and biomarkers, did not result in significantly better endoscopic outcomes at week 48 than symptom-driven decisions alone. 

Is endoscopy (and the SES-CD) the right target to shoot for? The debate around endpoints is more nuanced in CD given its complexity but this study was intently skewed towards what the endoscopist could see and luminal disease. If the inclusion criteria were ‘evidence of bowel wall thickening as seen on US/CT/MRE’ and then adjustment of ustekinimab based on a change of +/-2mm (for example) in small bowel wall thickness what might the results have looked like? What kind of patients might the study have recruited instead? 

Taking a holistic view of bowel wall healing beyond ulceration (despite being logical) is controversial and seemingly an anathema to the FDA who have resisted the move towards imaging endpoints in clinical trials. While recommended in various guidelines and widely used (with MaRIA being the best evidenced) imaging is not seeing much love in clinical trials. But for patient populations with L2/L3 disease, sophisticated drug companies may want to start looking to assets and claims really tailored to more specific sub-populations and the corresponding tests that excel in that space. I’m not advocating using MRE for distal UC here. 

Intestinal ultrasound has taken the EU by storm and is set to see fervent adoption in North America in the next few years. Ultrasound was used to perform a sub-study in 82 subjects from the trial with luke-warm results. Early response could be seen in as little as 4 weeks but a study built around endoscopy necessarily disadvantages imaging and vice versa and with subtle colonic disease being prevalent, ultrasound is on the back-foot (METRIC showed both MRE and US being weaker in the colon). 

Perhaps gastroenterologists are breathing a sigh of relief at a 16-week follow up endoscopy not being mandatory but the results of this study will make many of us go back and revisit trial design. It’s likely the existing tests we have need to be combined in new ways specific to the specific disease phenotype for the precision medicine ‘dream’ to be made real. IBD is on the edge of a technical revolution with AI, genetic testing, cloud computing, and cheaper more accessible tests being increasingly available. Having the role of endoscopy questioned, in an otherwise completely sensible concept (treat to target), is no bad thing and I profoundly hope this does not deter similar studies in the future. 

The Power Of Play

Before I worked at Motilent, I was a teaching assistant at a special needs school. Last week, when LEGO MRI scanners started popping up on social media, it made me think of the children I used to work with. For these children, who often struggle with communication, medical appointments can be very scary. MRI is a great non-invasive test, but what if your patient is too frightened to lie on the bed, or even to go into a hospital?

Motilent focuses on digestive disease, but we are especially passionate about paediatrics and adolescent health. 5000 children with gut issues are seen annually at Great Ormond Street Hospital alone, and children as young as a few months old can be diagnosed with Inflammatory Bowel Disease (IBD). Paediatric IBD incidence is as high as 14.3–18.3 per 100,000 in some Western countries. From my own experience, I suspect that the difficulty some children face communicating leads to symptoms being missed, leading to underdiagnosis and/or mismanagement.

MRI of small intestine. An exceptionally well behaved subject and a great example of a large intestinal contraction.

MRI is commonly used in IBD patients to establish where the disease is and what it’s doing. With this information, clinical teams can make more informed treatment decisions, helping put patients on the right treatment, at the right time. When we get this right, children with IBD can often avoid surgery for many years. However, without high quality diagnostic imaging of gut inflammation, symptoms will likely get worse with age.

Put yourself in the shoes of a child going to hospital for an MRI scan: The child will likely not be 100% sure why they are there, apart from the fact that they feel really poorly. Adding to the fact that hospitals are loud, they’re busy, they can smell, and are an altogether unfamiliar environment. The MRI scanner itself is a huge off-white-coloured doughnut, and the child will be asked to lie on a bed which slides them through a small, claustrophobic tunnel. Mum and Dad often can’t stay in the room and the headphones given to block out the hum of the machine — itch horribly. All this while being asked to remain perfectly still. It can be a horribly distressing experience.

Stress and anxiety about something you don’t understand is a normal reaction that’s not limited to children. From my experience working with children, many were really scared of any medical procedure even things like having their height and weight taken in the nurse’s room. Some find verbalising their feelings difficult and are unable to ask the questions that would help them feel safer.

These factors significantly increase the likelihood that scans last longer or have to be repeated, leading to a distressed child and potentially impacting treatment decisions.

But small interventions, such as giving children an MRI scanner made of LEGO, can help reduce anxiety in children in two vital ways:

  • Playing with different characters — a doctor, a technician, and a child preparing to be scanned — gives children the space to roleplay the scan and think through their feelings, but in a playful and less scary way.
  • The ability to open the scanner, and see what it looks like inside, can help children understand how the procedure works, and stop them worrying about the process, reassuring them of their safety.

Because of this, I’m delighted that the LEGO Group has tasked employees worldwide with building these MRI sets and donating them to local hospitals. 

We know fundamentally that children learn through play, which provides emotional support for them to understand and process their feelings and experiences. The LEGO MRI scanner (and who knows what toys in the future!) will help all children (and adults) become more familiar with the unknown, in hospital environments and beyond.

Beth Fisher (Product Specialist)