Are smokers protected from COVID-19?

29th May 2020

Over the years, public health campaigns have highlighted the dangers to health associated with smoking cigarettes and actively sought to discourage the practice.

Current data from the Office of National Statistics (ONS) from 2018 suggests that around 7.2 million adults smoke cigarettes which is a 5% decrease since 2011.1 While there several health benefits that accrue from smoking cessation, recent press reports seem to suggest that smokers are somehow protected from COVID-19.

Indeed, early reports from China on the clinical characteristics of patients admitted to hospital with COVID-19 found that the proportion of smokers was less than expected based on the estimated prevalence of smoking in the country which is 27.7%.2 For instance, in one study, the proportion of smokers was found to be considerably less than the average at 1.4%3 and while higher at 7% in another study,4 this was still lower than the average. Since these early reports from China, several other studies from different countries have also demonstrated that a lower than expected number of smokers have been hospitalised with COVID-19. In a study of those hospitalised with COVID-19 in New York, the prevalence of smokers was 5.1%5 which is less than half of the most recent estimate of the overall US smoking prevalence of 13.7%.6 Similarly, a retrospective analysis of 441 patients admitted to a hospital in northern Italy, found that less than 5% of patients were smokers, compared to an estimated age-adjusted prevalence of 14.9%.7 In a study of 340 patients in a French university hospital, it was found that 6.1% of patients were smokers compared to a population rate of 25.4%.8 Finally, in a yet to be peer-reviewed meta-analysis of available studies, Spanish researchers calculated that smokers were statistically less likely (odds ratio = 0.18, 95% CI 0.14 – 0.23) to be hospitalised for COVID-19.9

But are these observations simply a fluke or is there a plausible explanation that could account for the reduced incidence of COVID-19 among smokers?

One hypothesis proposes that it is nicotine which provides a degree of protection against the virus. This is based on an observation in 1990, that acute nicotine inhalation can increase both systolic and diastolic blood pressure and that this effect is mediated via an increase in angiotensin converting enzyme activity.10 In addition, other work has shown how the nicotine-induced rise in the level of ACE is also associated with a downregulation of the level of ACE-211 which is now considered to be a functional receptor for COVID-19 entry into cells.12 Other work has shown that nicotine is able to activate nicotinic acetylcholine receptors on immune cells and that this effect leads to an inhibition of the release of pro-inflammatory cytokines and protects against acute inflammation in lung tissue.13 While this appears to represent a rationale for how nicotine may be protective against COVID-19, other and more recent work published as a research letter to the European Respiratory Journal,14 found that in both smokers and those with COPD, there was an increased airway expression of ACE-2. The authors concluded that this offered a possible explanation as to why those with COPD are at an increased risk of infection but the data effectively countered the potentially protective role of nicotine. In an effort to untangle the association between smoking and COVID-19, an as yet non-peer reviewed analysis of 67 observational studies conducted in several different studies concluded that there is substantial uncertainty about the associations between smoking and COVID-19 outcomes.15 Moreover, an evidence review by Healthcare Improvement Scotland, also concluded that there is no significant association between smoking and severe disease.16 In contrast, the most recent meta-analysis of 19 peer-reviewed papers that included 11,590 patients concluded that smoking is a risk factor for the progression of COVID-19, with smokers having a higher odds of COVID-19 progression.17

In summary and based on the available evidence, it seems unlikely that smoking offers some degree of protection from the effects of COVID-19. The ONS report1 shows that smoking rates are the lowest at 7.9% in those 65 years and over and it is possible that the lower incidence of infection among smokers, simply reflects the fact that fewer older people smoke rather than an intrinsic and protective effect among smokers. Until more definitive evidence emerges, it would seem prudent that current healthcare advice to stop smoking is continued rather than patients relying on a potentially spurious belief that somehow smoking will prevent them from becoming infected with COVID-19.

References

1. Office for National Statistics. Adult smoking habits in the UK: 2018.
   www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/healthandlifeexpectancies/bulletins/adultsmokinghabitsingreatbritain/2018 (accessed May 2020).
2. Parascandola M, Xiao L. Tobacco and the lung cancer epidemic in China. Trans Lung Cancer Res 2019;8(S1):S21-S30.
3. Zhang JJ et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy 2020; Feb 19.
4. Huang C et al. Clinical features of patients infected with novel 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
5. Goyal P et al. Clinical characteristics of Covid-19 in New York City. N Engl J Med 2020; Apr 17.
6. Centers for Disease Control and Prevention. Smoking & Tobacco Use.
   www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_smoking/index.htm (accessed May 2020).
7. Gaibazzi N et al. Smoking prevalence in low in symptomatic patients admitted for COVID-19. MedRxiv 2020 doi.org/10.1101/2020.05.05.20092015
8. Miyara M, Tubach F, Pourcher V et al. Low rate of daily active tobacco smoking in patients with symptomatic COVID-19. Qeios 2020. www.qeios.com/read/WPP19W.4
9. Gonzalez-Rubio J et al. What is happening with smokers and COVID-19? A systematic review and meta-analysis. Preprints 2020; doi: 10.20944/preprints202004.0540.v1.
10. Calzado MCG et al. Tobacco and arterial pressure (II). The acute effects on the angiotensin-converting enzyme. Ann Med Intern 1990;7(8):392-5.
11. Oakes JM et al. Nicotine and the renin-angiostensin system. Am J Physiolo Regul Integ Comp Physiol 2018;315(5):R895-R906.
12. Kai H, Kai M. Interactions of coronavirus with ACE2, angiotensin II and RAS inhibitors-lessons from available evidence and insights into COVID-19. Hyptertens Rev 2020; doi.org/10.1038/s41440-020-0455-8.
13. Mabley J, Gordon S, Pacher P. Nicotine exerts and an anti-inflammatory effect in a murine model of acute lung injury. Inflammation 2011;34(4):231-7.
14. Leung JM et al. ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19. Eur Respir J 2020;55:20000688.
15. Simons D et al. The association of smoking status with SARS-CoV-2 infections, hospitalisation and mortality from COVID-19: a living rapid evidence review. Qeiosi. www.qeios.com/read/UJR2AW.4.
16. Healthcare improvement Scotland. Assessment of COVID-19 in primary care. https://eprints.gla.ac.uk/215857/1/215857.pdf (accessed May 2020).
17. Patanavanich R, Glantz SA. Smoking is associated with COVID-19 progression: a meta-analysis. Nicotine Tob Res 2020;May 13.

IL-17 a potential therapeutic target in chronic urticaria

Chronic spontaneous urticaria (CSU) is thought to be an autoimmune disorder in nearly half of all cases.

A combination of H1-antihistamines and the anti-immunoglobulin E (IgE) omalizumab have been used to manage the disease but this approach fails to provide adequate symptom control in up to 70% of patients, suggesting that there might be other and more appropriate therapeutic targets.

In this new and exploratory study by Israeli researchers, attention turned to interleukin (IL)-17, which has been shown to play an important role in other chronic and inflammatory autoimmune disorders including psoriasis, rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis. The rational for targeting IL-17 arises from evidence showing that elevated levels of the cytokine have been found in the serum of those with CSU and that higher levels are positively correlated with disease severity.

A total of eight patients with severe, treatment resistant CSU were given the anti-IL-17 monoclonal antibody, secukinumab, at a dose of 150mg weekly for four consecutive weeks and then 150mg every fortnight for a total of 90 days. Patients were assessed after 30 days at which point disease activity was reduced by 55% compared with baseline but had reduced by 82% after three months in all patients. Though the authors plan to conduct a larger study they concluded that secukinumab may be an effective therapy for treatment-resistant cases of CSU.

Reference
Sabag DA et al. Interleukin-17 is a potential player and treatment targer in sever chronic spontaneous urticaria. Clin Exp Allergy 2020; May 15 doi: 10.1111/cea.13616.

New insight of the causes of an allergic reaction raises hope for treatment

Internationally, allergies affect around one-third of the population.

Central to the development of an allergic reaction is the binding of an allergic-specific immunoglobulin E (IgE) with the allergen on the surface of mast cells and the subsequent release of several allergic mediators.

However, although IgE is an essential component of the allergic reaction, it remains unclear how allergies to certain substances such as peanuts, develop in some, but not all patients, despite the presence of the same specific IgE antibodies in their blood. 

Now a team from the USA has compared the IgE from individuals with and without a peanut allergy and found that the allergic response is mediated by the presence of sialic acid, a sugar residue, attached to the specific IgE. The researchers determined that sialic acid was a strong predictor of allergic disease and that removal of the sugar led to an attenuation of the allergic response. In addition, rather than simply removing the sialic acid, the researchers attached a neuraminidase enzyme to the IgE receptor, which blocked the action of the acid and noted that this also significantly minimised the allergic reaction.

While further work is required to more fully clarify the role of sialic acid in the generation of an allergic response remains to be clarified, it is possible that targeting the sugar moiety might represent a future therapeutic strategy for those with allergies.

Reference

Shade KTC et al. Sialylation of immunoglobulin E is a determinant of allergic pathogenicity. Nature 2020; May 20 doi.org/10/1038/s41586.

Children and COVID-19: is it safe to return to school?

27th May 2020

Much has been made of the UK government’s plans to reopen schools in June although there has been much concern expressed by parents and some local authorities that this move is far too soon.

The intention to open schools is based on the premise that children are unlikely to pass on the virus to either other children or adults but how robust is the evidence used to support this claim?

There has been a great deal of research on this topic that has been quickly published online though most of it has not been subject to peer review. One review of the preliminary evidence suggested that children were just as likely as adults to become infected with COVID-19 but also that children less liable to be symptomatic or to develop severe symptoms.1 In an analysis of just over 2000 Chinese children (median age 7 years) infected with COVID-19 during the early stages of the pandemic, it was found that 94% were either asymptomatic or had mild to moderate symptoms although the authors concluded that children of all ages were susceptible to the virus.2 The fact that mortality is considerably less in children in borne out by the latest Office for National Statistics (ONS) report which showed that up to the 8 May, of the 37,375 COVID-19 recorded deaths in the UK, only three have occurred in those between the ages of 1 and 14.3 Furthermore, in a community testing study in Vo, Italy (which has not been subject to peer review) in which nasopharyngeal swabs were collected from between 71 and 86% of the eligible population in all age groups, no infections were found in children aged between 0 and 10 years, despite the fact that they lived in the same house as infected people.4 Despite this, the latest data from the ONS infection survey observed no difference in the proportion testing positive between age categories.5 For instance, the report shows that 0.26% of those in the age category 2–11 tested positive, compared with 0.32% in those aged 70 years and over.

The ONS data provides valuable insight of the positivity rate but says nothing about the prevalence rate, that is, the number of people who actually develop COVID-19 symptoms. Some understanding of the prevalence rate can be determined by examining what researchers term the “attack rate”, in other words, the proportion of people who become infected after contact with someone has tested positive. One Chinese study assessed 1286 contacts of 391 index cases (that is, those who had tested positive) and found that the attack rate was 7.4% in children under 10 years of age compared to the population average of 6.6%.6 In another Chinese study, the observed attack rate in children was 5.26% which was considerably lower than the rate of 17.69% in those aged 60 years and over.7 Finally, in a review of Chinese contract tracing surveys it was found that the odds ratio for infection in those aged 0–14 years was 0.34 (95% CI 0.24 –0.49) compared to an odds ratio of 1.47 (95% CI 1.12–1.92) in those aged 65 years and over.8

Whilst the above information indicates that children can become infected, a much more relevant question, especially in relation to the reopening of schools, is how easy is it for infected children to pass on the virus? Unfortunately, this is a much more difficult question to answer, although emerging evidence does offer some hope that transmission of the virus from children is less likely. In a report from New South Wales, Australia, it was found that in a total of six confirmed infections (one child and five staff), there were a total of 168 contacts of which only one individual became infected. The report also concluded that the authors found no evidence of children infecting teachers.9 Further reassurance that transmission from children is improbable comes from a French study in which a child to tested positive for COVID-19 did not transmit the virus to anyone else despite their interaction with a large number of contacts.10

In summary, it appears that although children can contract the virus just as easily as adults, the severity of the illness is much less. In addition, while the available data is limited, it does seem that infected children are less liable to pass on COVID-19 and this should offer some reassurance to parents who are concerned about sending their offspring back to school in the near future.

References

1. Zimmermann P, Curtis N. Coronavirus infection in children. Pediatr Infect Dis J 2020;39:355-68.
2. Dong Y et al. Epidemiology of COVID-19 among children in China. Pediatrics 2020; Apr 2020.
3. Office for National Statistics. Deaths involving COVID-19 up to 8 May.
   www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/coronaviruscovid19roundup/2020-03-26#coviddeaths (accessed May 2020).
4. Lavezzo E et al. Suppression of COVID-19 outbreak in the municipality of Vo, Italy. MedRxiv 2020 https://doi.org/10.1101/2020.04.17.20053157
5. Office for National Statistics. Coronavirus (COVID-19) Infection survey pilot: England, 21 May 2020.
   www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/coronaviruscovid19infectionsurveypilot/england21may2020 (accessed May 2020).
6. Bi Q et al. Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study. Lancet infect Dis 2020;Apr 27;S1473.
7. Jing Q et al. Household secondary attack rate of COVID-19 and associated determinants. MedRxiv 2020; Apr 15: doi: 10.1101/2020.04.11.20056010.
8. Zhaung J, Litvinova M, Liang Y et al. Changes in contact patterns shape the dynamics of the COVID-19 outbreak in China. Science 2020 Apr 29. Eabb8001.
9. NCIRS. COVID-19 in schools – the experience in NSW. http://ncirs.org.au/sites/default/files/2020-04/NCIRS%20NSW%20Schools%20COVID_Summary_FINAL%20public_26%20April%202020.pdf (accessed May 2020).
10. Danis K et al. Cluster of coronavirus disease 2019 (COVID-19) in the French Alps. Clin Infect Dis 2020; Apr 11: doi: 10.1093/cid/ciaa424.

Commentary: Cow’s milk allergy the most significant burden in children with multiple allergies

22nd May 2020

Globally food allergies affect around 10% of children and in around 70% of cases, children actually have multiple allergies which creates a huge health burden that negatively impacts on quality of life.

In a recent study, an online questionnaire was distributed to families of children with a physician diagnosed milk allergy plus at least one other food allergy. The questionnaire set out to explore the allergy burden terms of time, financial costs, social restrictions and emotional demands. After completing the questionnaire, a subset of parents were interviewed to provide a greater insight of the allergy burden.

64 participants were recruited with over 70% of the children aged 10 or younger. In addition to milk, other reported allergies included peanuts (65%), tree nuts (58%), egg (76%) and sesame (31%). Milk allergy was reported as being the most socially limiting (81%), required the most planning (76%) and caused the most anxiety (68%). In the subsequent interviews, parents reported on how alternative sources of calcium were both difficult to find and costly and also perceived as not having the same nutritional value. Other problems identified included how milk was heavily promoted to children as a dietary staple and that dairy-related ingredients were ever-present which made eating at restaurants challenging.

Reference
Abrams EM et al. Milk allergy most burdensome in multi-food allergic children. Pediat Allerg Imm-UK 2020;15 May doi.org/10.1111/pai.13274

Are inhaled corticosteroids safe in those with COVID-19?

There is a good deal of evidence to show that as much as 80% of asthma and between 40 and 60% of COPD exacerbations have a viral cause.1

Furthermore, in the original work from China, it was found that those with an underlying lung problem and who were hospitalised, had a worse prognosis.2

Improvements in asthma therapeutics have led to reductions in mortality as witnessed by a Canadian study in 2000 which observed that regular low dose inhaled corticosteroids (ICSs) were associated with a reduced risk of asthma deaths.3 Moreover, other work has found that the addition of a long-acting beta-agonist such as salmeterol to an ICS regime reduced both the number and severity of asthma exacerbations.4 While these drugs are clearly effective at controlling asthma and COPD, and that stopping them will undoubtedly risk a disease exacerbation, a more relevant question given the high prevalence of viral-induced asthma and COPD, is whether ICSs, which have an immunosuppressive action, should be continued during the COVID-19 pandemic? The available evidence, at least based on studies with rhinoviruses, points to an increased risk of respiratory infections with these drugs.

In a recent meta-analysis, Yang et al found that the use of ICSs significantly increased the risk of upper respiratory tract infections (URTI) in those with asthma, irrespective of the dose.5 The same group also observed that high dose ICSs increased the risk of URTI in patients with COPD and that there was a non-significant increase in risk from lower doses.6 In a Cochrane review of ICS use in COPD, it was found that although ICSs reduce the risk of exacerbations and the decline in quality of life, there was also an increases risk of pneumonia.7 Although the evidence for asthma is less clear, a case-controlled study observed an increased risk of pneumonia or lower respiratory tract infections among patients using ICS.8

Exactly how ICSs increase the risk of infections is still not clear though possible mechanisms include reduced production of antiviral interferon9 and an ICS-induced impaired innate and acquired immune response combined with delayed viral clearance.10 In contrast, however, not all studies point to worse outcomes and one study in patients with asthma, found that ICSs did not interfere with the normal preventative viral-induced inflammatory response to infection.11

Given the potential of ICSs to increase the risk of infections, should these treatments be stopped or continued if patients develop COVID-19? A recent review of the literature has concluded that ICS can be continued in patients with COVID-19.12 The authors identified 771 publications although none were found to have data on prior ICS use in patients with several viruses including SARS, Middle East respiratory syndrome (MERS) or even the current COVID-19 infection. In the absence of any obvious harm, the authors suggested that there is currently no reason to stop ICSs in patients with either asthma or COPD who are stable. Although stopping these drugs would clearly increase the risk that either condition would worsen, equally, the current review does not provide any definitive evidence that continued use of ICSs during an infection with COVID-19 is NOT associated with harm, especially given the increased risks associated with infection from rhinoviruses.8-10 While it can be argued that coronaviruses are not the same as rhinoviruses, it does seem somewhat curious that there are currently two ongoing clinical trials exploring the value of inhaled corticosteroids13 and the combination of other inhaled corticosteroids and long-acting beta-agonist14 in patients with COVID-19 infection and that these trials are based on in vitro evidence that the combination of an ICS and long-acting beta-agonist were able to curtail excessive inflammation induced by rhinovirus infections.15

In summary, it seems that the current review by Halpin et al12 does not really provide any useful information on whether ICSs should be either continued or stopped during the current pandemic. In many of the rapid COVID-19 guidelines from NICE, it is recommended that ICSs are continued.16 In trying to interpret this review, health professionals should take heed of the aphorism that “absence of evidence is not evidence of absence.”

References

1. Johnston SL. Overview of virus-induced airway disease. Proc Am Thorac Soc 2005; 2(2):150–6.
2. Huang C et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497–506.
3. Sussa S et al. Low-dose inhaled corticosteroids and the prevention of death from Asthma. N Engl J Med 2000;343(5):332–6.
4. Matz J et al. Addition of salmeterol to low-dose fluticasone versus higher-dose fluticasone: an analysis of asthma exacerbations. J Allergy Clin Immunol 2001;107(5):783–89.
5. Yang M et al. Inhaled corticosteroids and risk of upper respiratory infection in patients with asthma: a meta-analysis. Infection 2019;47:377–85.
6. Yang M et al. Long-term use of inhaled corticosteroids and risk of upper respiratory tract infection in chronic obstructive pulmonary disease: a meta-analysis Inhal Toxicol 2017;29(5):219–26.
7. Yang IA et al. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012;7:CD002991.
8. McKeever T et al. Inhaled corticosteroids and the risk of pneumonia in people with asthma: a case-control study. Chest 2013;144(6):1788–94.
9. Simpson JL et al. Reduced antiviral interferon production in poorly controlled asthma is associated with neutrophilic inflammation and high-dose inhaled corticosteroids. Chest 2016;149:704–13.
10. Singanayagam A et al. Corticosteroid suppression of antiviral immunity increased bacterial loads and mucus production in COPD exacerbations. Nat Commun 2018;9(1):2229.
11. Southworth T et al. Increased type 2 inflammation post rhinovirus infection in patients with moderate asthma. Cytokine 2020;125:154857.
12. Halpin DMG, Singh D, Hadfield RM. Inhaled corticosteroids and COVID-19: a systematic review and clinical perspective. Eur Respir J 2020;55:2001009.
13. A trial of ciclesonide in adults with mild COVID-19. https://clinicaltrials.gov/ct2/show/NCT04330586 (accessed May 2020).
14. Protective role of inhaled steroids for COVID-19 infection. https://clinicaltrials.gov/ct2/show/NCT04331054 (accessed May 2020).
15. Davies JM et al. Budesonide and formoterol reduce early innate anti-viral immune responses in vitro. PLoS One 2011;6:e27898.
16. NICE. COVID-19 rapid guideline: community-based care of patients with chronic obstructive pulmonary disease (COPD). NG168. www.nice.org.uk/guidance/ng168 (accessed May 2020).

Loss of smell added to list of COVID-19 symptoms

In a statement from the UK Chief Medical Officer, it was advised that from 18 May, anyone who experiences a fever, persistent cough or anosmia (loss of smell), should self-isolate.

Evidence that anosmia might be an important symptom of COVID-19 has been highlighted in a press release by ENTUK which cites an increasing number of reports from different countries which suggest that loss of taste and smell are likely to be important symptoms of infection. For instance, one study from Germany found that among 200 COVID-19 positive patients, two in three reported loss of smell and taste. In addition, the mostrecent update from the COVID-19 symptom study in which patients have been using an app to document symptoms, suggest that losing a sense of taste and smell is a stronger predictor of COVID-19 infection than fever. Exactly how the virus causes these symptoms remains a mystery but one theory is that the virus causes inflammation in the olfactory epithelial cells which relay information on taste and smell to the brain.

Nevertheless, the recent deluge of research papers linking anosmia to COVID-19 would suggest that it is an important symptom that should not be ignored in assessing patients who might be infected.

Commentary: Increased risk of herpes zoster in patients prescribed JAK inhibitors

Janus kinase inhibitors (JAKIs) are being increasingly used to treat conditions such as inflammatory and immune-mediated diseases.

JAKIs are known to give rise to serious adverse effects such as herpes zoster and in a recent systematic review, researchers attempted to assess the relative risk of adverse events that arise with these drugs. The analysis included 82 studies, two-thirds of which were randomised trials and comprised 66,159 patients. The primary outcome was the incidence rates of both adverse events (AEs) and serious adverse events (SAEs). The majority of studies were in patients with rheumatoid arthritis (53/82) although other conditions included psoriasis, inflammatory bowel disease and ankylosing spondylitis. The median exposure time to a JAKI was 26 weeks although there was a wide variability in treatment duration between studies.

The relative risk of AEs was 1.01 (0.97–1.06) and 0.98 (0.83–1.1.5) for SAEs. The relative risk of herpes zoster infection was 1.57 (1.04 – 2.37) which appeared to be a class effect and was significantly higher than for all other AEs.

The authors concluded that JAKIs increased the risk of herpes zoster compared to other adverse effects and called for more real-world studies of longer duration to fully establish the adverse effect profile of this new class of drugs.

Reference
Olivera PA et al. Safety of Janus Kinase inhibitors in patients with inflammatory bowel diseases or other immune-mediated diseases: a systematic review and meta-analysis. Gastroenterology 2020;158(6):1554-73.

Preserving inflammation-free phases in Crohn’s disease

19th May 2020

Intestinal stem cell metabolism is facilitated by mitochondria and chronic inflammation processes inhibit the cells’ metabolism and lead to functional loss of these stem cells.

In collaboration with the Helmholz Zentrum München and the Université de Paris, a research team at Technical University of Munich has discovered this connection by analysing intestinal epithelial cells of Crohn’s disease patients and comparing them to mouse model findings.

Stem cells are indispensable for the maintenance and regeneration of tissues. Intestinal stem cells inside the intestines are intermingled with so-called Paneth cells, which are responsible for the local immune defence and for creating an environment in which the stem cells can prosper, thus termed guardians of the stem cell niche.

Patients suffering from Crohn’s disease have fewer Paneth cells and furthermore, these are limited in their functionality. The research group examined the causes for alterations in Paneth cells and attempted to determine the importance of stem cell metabolism in this context.

In addition to mouse studies, the researchers analysed intestinal biopsies from Crohn’s disease patients, characterising the stem cell niche meticulously. After six months, the patients’ intestines were examined again endoscopically focusing on finding signs of inflammation.

The study showed that microscopic alterations in stem cell niche were particularly prevalent in those patients who showed symptoms of a relapse of inflammation after six months.

“These changes in the stem cell niche are a very early indicator for the start of inflammatory processes. Therefore, the appearance of the stem cell niche can be used to evaluate the probability of a disease recurrence after the resection of originally affected parts of the small intestine. This presents a reasonable starting point for therapeutic intervention,” explained Dirk Haller, Professor for Nutrition and Immunology at TUM.

In both human patients and mouse models, alterations in Paneth and stem cells coincided with decreased mitochondria functionality.

Knowing that a lowered mitochondrial respiration leads to alterations in the stem cell niche, the researchers used dichloracetate (DCA), a substance applied in cancer therapy leading to an increase in mitochondrial respiration.

The shift in cellular metabolism induced by DCA was able to restore the intestinal stem cell functionality of mice suffering from inflammation, as demonstrated in intestinal organoids, organ-like structures cultured ex vivo.

“These findings point to a new therapeutic approach for prolonging the inflammation-free remission phases of Crohn’s disease,” said Eva Rath, scientist at the TUM School of Life Sciences Weihenstephan and co-author of the study.

The aim of further research is to investigate the effect of DCA in animal models and patients in more detail. A so-called metabolic intervention — making targeted changes in the cells’ metabolism — could prevent functional loss of stem cells and Paneth cells, which both maintain the intestinal barrier. This could lead to preventing subsequent inflammation.

Link between IBD and coeliac disease established

Researchers have established a connection between inflammatory bowel disease (IBD) and coeliac disease.

A systematic review and meta-analysis at the Farncombe Family Digestive Health Research Institute at McMaster in collaboration with the Society for the Study of Celiac Disease has determined there is a nine-fold increased risk of having IBD for patients with a previous diagnosis of coeliac disease. Similarly, the risk for coeliac disease is increased in IBD patients, though to a smaller extent.

The details were published in Gastroenterology.

“Clinicians have always suspected that IBD and coeliac disease may be linked, however a clear association was never established,” said first study author Maria Ines Pinto-Sanchez, associate professor of medicine and member of the Farncombe Family Digestive Health Research Institute at McMaster.

“This is important, as failure to diagnose one or the other condition could compromise proper response to available treatments. It also raises questions on screening for the other disease in a patient already diagnosed with either IBD or coeliac disease.”

IBD and coeliac disease are chronic and disabling intestinal conditions affecting many Canadians as Canada has one of the highest frequencies of IBD in the world. Both diseases share similar risk factors and their prevalence has increased in the past years.

While the exact cause of IBD is unknown, it is accepted that infections, genes and other environmental factors are involved. The main environmental trigger for coeliac disease is dietary gluten, but specific genes are required to develop the condition.

The researchers identified 9800 studies and included 65 studies in their analysis. Of those, 30 studies included control groups with a total of 13.6 million participants, including: 43,000 celiac patients, 166,000 IBD patients (39,000 Crohn’s, 56,000 ulcerative colitis, and 3000 indeterminate colitis patients), and 13.4 million controls.

The studies were published between 1978 and 2019. Forty-three studies were conducted in adults, 12 studies in children, and 9 studies in all ages. The majority of the studies were in Europe, followed by North America and Asia.

The researchers suggest the next step is to determine whether testing for the diseases is cost-effective and beneficial to patients.

“Our review has confirmed that there is a strong association between celiac disease and IBD, but at this time, it is unclear whether screening of IBD should be performed in coeliac disease and vice versa,” said corresponding study author Elena Verdu, professor of medicine and scientist of the Farncombe Family Digestive Health Research Institute at McMaster.

“More studies into the association of IBD and coeliac disease are needed, as this could lead to screening and therapeutic interventions to improve patient outcomes.”