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The COVID-19 Vaccination Debate: COVID-19 and Celiac Disease

Hugh J. Freeman
International Journal of Celiac Disease. 2021, 9(1), 3-5. DOI: 10.12691/ijcd-9-1-7
Received January 02, 2021; Revised January 15, 2021; Accepted January 21, 2021

Abstract

COVID-19 is a novel coronavirus that appears to cause a systemic disorder largely marked by fever and respiratory symptoms as well as diarrhea. The agent gains access to respiratory and gastrointestinal cells through a complex molecular mechanism associated with increased ACE2 receptor expression on brush border membranes of epithelial cells. Because some autoimmune-based disorders, including celiac disease, appear to be at increased risk for viral and community-acquired bacterial infections, a number of preliminary survey studies from different countries, largely web-based or telephone-based, have suggested that COVID-19 infection risk is not increased in celiac disease. However, specific sub-groups of patients with celiac disease have not been thoroughly evaluated. For example, selective immunoglobulin A deficiency or other immune deficiency states with celiac disease may represent a special risk group for COVID-19 and other viral infectious agents.

1. COVID-19 and other Coronavirus Agents

COVID-19 (or SARS-CoV-2) is a newly recognized coronavirus initially reported from Wuhan, Hubei Province, China in late 2019. This was mainly associated with a severe form of pneumonia 1. After global spread to over 100 countries, the World Health Organization declared a pandemic due to a highly infectious single-stranded, positive-sense RNA virus, sometimes fatal 2. Similarities were noted with the severe respiratory syndrome outbreaks (SARS and MERS) previously recorded from Guangdong Province, China 3, 4, 5 as well as the Middle East, specifically Saudi Arabia 6. All of these coronavirus agents may be transmitted largely by droplet-contact transmission and the incubation period is estimated to be days to about 2 weeks 7. Recently, a so-called “UK Variant” of SARS-CoV-2 has been also noted, perhaps even more highly infectious than the first COVID-19 agent.

To date, millions have been infected globally with COVID-19, while the other 2 agents have been estimated to have infected thousands with death rates for COVID-19 estimated to be about 3 to 4% compared to about 10% to 30% for the other earlier coronavirus agents 7. For all, the natural animal reservoir appears to be the bat with possibly different intermediate hosts (pangolin?, civets, camel) 7. Besides non-specific “flu-like” symptoms (eg., fever and chills, headache and myalgias), clinical disease has largely been attributed to respiratory tract involvement (eg., cough, dyspnea, respiratory distress), and, as noted previously in this journal 8, 9, however, prominent gastrointestinal symptoms may occur, including diarrhea.

2. Coronavirus Diarrhea

Indeed, all 3 of these recently described agents may cause diarrhea, sometimes profound and associated with nutrient malabsorption. Detailed microscopic studies using immunofluorescence methods and ultrastructural studies used to identify these viruses have documented the agents in intestinal tract epithelium and luminal fecal material, raising the possibility of an alternate oral-anal route for transmission 7, 10, 11. Interestingly, some polymerase chain reaction (PCR) studies demonstrated that patient fecal material remained persistently positive, even after respiratory tract viral shedding had ceased, suggesting a possible ongoing source of shedding in fecal material 11.

With COVID-19, evidence for viral host receptor ACE2 in epithelial cell cytoplasm was shown with immunofluorescent staining in gastric and intestinal epithelium of patients with positive fecal studies 11, 12, 13, 14. In addition, viral nucleocapsid protein could be demonstrated suggesting that the ACE2 receptor was a potentially important route for epithelial cell entry and later assembly of new virions for luminal shedding. Previous studies had also suggested that SARS-CoV could enter gastric and intestinal mucosa by interaction between an envelope anchored spike glycoprotein of the virus and ACE2 receptors on the apical surface (or brush border microvillus membrane) in gastric and intestinal epithelial cells. Spike protein subunits are thought to mediate both host epithelial cell membrane attachment and fusion. Cellular serine proteases (TMPRSS2), highly expressed in epithelial cells, initiate spike protein cleavage to regulate the process with infectivity dependent on ACE2 binding affinity (SARS-Cov-2 estimated to be 10 to 20 times greater than SARS-Cov) 7, 15. It has also been estimated that the ACE2 receptor is abundantly expressed by a factor of 100 or more compared to respiratory epithelial cells 7. Some believe that this may lead to altered intestinal permeability and abnormal nutrient absorption 16, 17. Other changes may lead to impaired amino acid and peptide absorption as well as alterations in the gut microbiome 17.

3. Role in Intestinal Diseases

Patients with underlying intestinal diseases may be at increased risk for COVID-19 disease, particularly in patients with inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease. Although intestinal symptoms of diarrhea were initially considered to reflect a more severe illness with COVID-19, more recent studies have suggested that intestinal symptoms may precede or occur independently without any respiratory symptoms. More and more, these patients with inflammatory bowel disease are also being treated with long-term immune suppressive pharmaceutical agents as well as biological agents. Furthermore, some of these patients may be more susceptible to viral infectious agents 18. There is concern in this patient group for development of severe COVID-19 disease, including an increased COVID-19 mortality, but this hypothesis remains controversial and unproven 19. It has been suggested that a second form of ACE2 may be present in patients with inflammatory bowel disease, both a membranous ACE2 type as well as a soluble form 19. In patients with inflammatory bowel disease, a high level of soluble ACE2 may prevent enteric viral interaction with the membranous ACE2 and even lead to a reduction in severity of COVID-19 disease 19, 20, 21. Additional studies are needed.

4. Role in Celiac Disease

Information in celiac disease is very limited, in large part, because of the extreme difficulty in conducting direct patient-based clinical research in this environment. As a result most published studies are based on clinical cases and web-based surveys. In addition, much data available is largely related to “in press” publications that have not had the benefit of more extensive peer review of readers. Indeed, Emmi et al 22 noted that an Italian cohort with autoimmune disorders and treated with different immune suppressant agents did not appear to have an increased risk of SARS-CoV-2 infection compared to the general population. It was also noted that there was an increased risk of hospitalization with influenza infections in Swedish patients with celiac disease 23 as was the risk of community acquired pneumonia in Italian celiac disease patients 24, 25, however, an increased risk of COVID-19 infection could not be confirmed in a telephone survey of 138 Italian adult celiacs on a gluten-free diet 26. Similar findings were noted in a group of 101 celiac patients based on telephone and email contact 27. Although the risk of a COVID-19 diagnosis was not increased in Turkish celiacs, access to gluten-free products was significantly reduced 27. In contrast, a web-based survey of Italian celiacs suggested that adherence to a gluten-free diet was actually improved, particularly in those with prior difficult disease control 28. In another study using a remote consultation approach based on an email survey of 276 responses in Italian celiacs, there was some concern expressed on gluten-free diet access by elderly patients, females and those with other co-morbidities, but most participants were pleased with this remote consultation mechanism to celiac disease management 29. Although delay in diagnosis of celiac disease was noted in one report 30, the prevalence rate of COVID-19 in a study from Lombardy 31 was 2.78%, no different from the general population. Clinical features, age, sex, duration, gluten-free diet adherence and mucosal healing did not differ in celiac patients with and without COVID-19. None of their 9 patients (of 324) in this study required hospitalization suggesting that COVID-19 disease course in celiac disease was mild. Similarly, in a series of 21 patients labeled with refractory disease from Milan, contacted after a 2-month period of lockdown, no complicating COVID-19 infections were reported 32.

A recent multi-center survey type study from multiple countries evaluated 18,022 participants, but over 10,000 were self-reported with no biopsy 33. In this report, the risk of contracting COVID-19 was not increased leading the investigators to conclude that there was no need to assume added precautions to prevent exposure beyond that recommended to the general public.

Although these studies, largely web-based or telephone-based, have not been able to define an increased risk for COVID-19 infection in celiac disease, added studies are needed and there may be specific celiac sub-groups that are at higher risk. For example, adults with celiac disease may also present with concomitant immunoglobulin A deficiency 34. Importantly, there may be a crucial association between the presence of selective IgA deficiency and COVID-19. Although a gluten-free diet may improve the pathologic features in celiac disease, the diet may also lead to a minimally improved level of IgA in celiac patients with immunoglobulin A deficiency 34. It seems conceivable that an increased risk for different infectious agents, including COVID-19, may occur in this setting, particularly since small bowel epithelial cells may be seeded with this virus during a systemic infection. Added studies of this particular celiac population group and possible role, if any, of small bowel epithelial IgA may be useful to determine risk of COVID-19.

In conclusion, initial studies have been hindered by limited numbers of confirmed celiac disease patients and further longer term studies are still needed to determine if celiac disease truly represents a concern for increased COVID-19 risk, including patients that fail to expeditiously respond to a gluten-free diet.

References

[1]  Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497-506.
In article      View Article
 
[2]  World Health Organization. Coronavirus disease (COVID-19) outbreak (http://www.who.int).
In article      
 
[3]  Zhuong NS, Zheng BJ, Li YM, et al. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People’s Republic of China, in February 2003. Lancet 2003; 363: 1353-1358.
In article      View Article
 
[4]  Ksiazek TG, Erdman D, Goldsmith CD, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 2003; 348: 1953-1966.
In article      View Article  PubMed
 
[5]  Drosten C, Gunther S, Preiser W, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003; 348: 1967-1976.
In article      View Article  PubMed
 
[6]  Zaki AM, van Boheemen S, Bestebroer TM, et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012; 367: 1814-1820.
In article      View Article  PubMed
 
[7]  Meng X, Lou Q-y, Yang W-y, et al. Gordian knot: gastrointestinal lesions caused by three pathogenic coronaviruses from SARS-CoV and MERS-CoV to SARS-CoV-2. Europ J Pharmacol 2021; 890: 173659.
In article      View Article  PubMed
 
[8]  Freeman HJ. COVID-19 diarrhea. Int J Celiac Disease 2020; 8: 60-63.
In article      
 
[9]  Lerner A. Covid-19 and the human gut: a new runner on the tract. Int J Celiac Disease 2020; 8: 64-67
In article      
 
[10]  Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; 382: 929-936.
In article      View Article  PubMed
 
[11]  Xiao F, Tang M, Zheng X, et al. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 2020; 158:1831-1833.
In article      View Article  PubMed
 
[12]  Zhou P, Yang L, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579: 270-273.
In article      View Article  PubMed
 
[13]  Harmer D, Gilbert M , Borman R, et al. Quantitative mRNA expression profiling of ACE2, a novel homologue of angiotensin covering enzyme. FEBS Lett 2002; 532: 107-110.
In article      View Article
 
[14]  Yan R, Zhang Y, Li Y, et al. Structural basis for the recognition of SARS-Cov-2 by full length human ACE2. Science 2020; 367: 1444-1448.
In article      View Article  PubMed
 
[15]  Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; In press.
In article      View Article  PubMed
 
[16]  Gu J, Han B, Wang J. COVID-19: gastrointestinal manifestations and potential fecal-oral transmission. Gastroenterology 2020; 158: 1518-1519.
In article      View Article  PubMed
 
[17]  Hashimoto T, Perlot T, Rehman A, et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 2012; 487: 477-481.
In article      View Article  PubMed
 
[18]  Monteleone G, Ardizzone S. Are patients with inflammatory bowel disease at increased risk for Covid-19 infection? J Crohn’s and Colitis 2020; 14: 1334-1336.
In article      
 
[19]  Meghool F, Valiani A, Safari T, et al. Gastrointestinal and renal complications in SARS-CoV-2 infected patients: role of immune system. Scans J Immunol 2020; 00: e12999.
In article      View Article  PubMed
 
[20]  Burgueno JF, Reich A, Hazime H, et al. Expression of SARS-CoV-2 entry molecules ACE2 and TMRSS2 in the gut of patients with IBD. Inflammatory Bowel Dis 2020; 26: 797-808.
In article      View Article  PubMed
 
[21]  Neurath MF. COVID-19 and immunomodulation in IBD. Gut 2020: 69: 1335-1342.
In article      View Article  PubMed
 
[22]  Emmi G, Bettiol A, Mattioni I, et al. SARS-CoV-2 infection among patients with systemic autoimmune disease. Autoimmunity Rev 2020; 19: 102575.
In article      View Article  PubMed
 
[23]  Marild K, Fredlund H, Ludvigsson JF. Increased risk of hospital admission for influenza in patients with celiac disease: a nationwide cohort study in Sweden. Am J Gastroenterol 2010; 105: 2465-2473.
In article      View Article  PubMed
 
[24]  Zingone F, Abdul Sultan A, Crooks CJ, et al. The risk of community-acquired pneumonia among 9803 patients with celiac disease compared to the general population: a cohort study. Aliment Pharmacol There 2016; 44: 57-67.
In article      View Article  PubMed
 
[25]  Canova C, Ludvigsson J, Baldo V, et al. Risk of bacterial pneumonia and pneumococcal infection in youths with celiac disease—a population-based study. Dig Liver Dis 2019; 51: 1101-1105.
In article      View Article  PubMed
 
[26]  Zingone F, D’Odorico A, Lorenzon G, et al. Risk of COVID-19 in celiac disease patients. Autoimmunity Rev 2020; 19: 102639.
In article      View Article  PubMed
 
[27]  Gokden Y, Hot S, Adas M, et al. Celiac disease and COVID-19 pandemic: should we worry? Acta Gastroenterol Belg 2020; 83: 517-525.
In article      
 
[28]  Monzani A, Lionetti E, Felici E, et al. Adherence to the gluten-free diet during the lockdown for COVID-19 pandemic: a web-based survey of Italian subjects with celiac disease. Nutrients 2020; 12: 3467.
In article      View Article  PubMed
 
[29]  Siniscalchi M, Singole G, Savarino EV, et al. COVID-19 pandemic perception in adults with celiac disease: an impulse to implement the use of telemedicine. Dig Liver Dis 2020; 52: 1071-1075.
In article      View Article  PubMed
 
[30]  Catassi GN, Vallorani M, Cerloni F, et al. A negative fallout of COVID-19 lockdown in Italy: life-threatening delay in the diagnosis of celiac disease. Dig Liver Dis 2020; 52: 1092-1093.
In article      View Article  PubMed
 
[31]  Schiepatti A, Alimenti E, Naimaris S, et al. Prevalence, incidence and clinical features of SARS-CoV-2 infection in adult celiac patients. Eur J Gastroenterol Hepatol 2021; In press.
In article      View Article  PubMed
 
[32]  Elli L, Scaramella L, Lombardo V, et al. Refractory celiac disease and COVID-19 outbreak: findings from a high incidence scenario in Northern Italy. Clin Res Hepatol Gastroenterol 2020; 44: e115-e120.
In article      View Article  PubMed
 
[33]  Freeman HJ. Biopsy-defined adult celiac disease and selective immunoglobulin A deficiency. Int J Celiac Disease 2017; 5: 10-13.
In article      
 
[34]  Naito Y, Takagi T, Yamamoto T, et al. Association between selective IgA deficiency and COVID-19. J Clin Biochem Nutr 2020; 67: 122-125.
In article      View Article  PubMed
 

Published with license by Science and Education Publishing, Copyright © 2021 Hugh J. Freeman

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Cite this article:

Normal Style
Hugh J. Freeman. The COVID-19 Vaccination Debate: COVID-19 and Celiac Disease. International Journal of Celiac Disease. Vol. 9, No. 1, 2021, pp 3-5. http://pubs.sciepub.com/ijcd/9/1/7
MLA Style
Freeman, Hugh J.. "The COVID-19 Vaccination Debate: COVID-19 and Celiac Disease." International Journal of Celiac Disease 9.1 (2021): 3-5.
APA Style
Freeman, H. J. (2021). The COVID-19 Vaccination Debate: COVID-19 and Celiac Disease. International Journal of Celiac Disease, 9(1), 3-5.
Chicago Style
Freeman, Hugh J.. "The COVID-19 Vaccination Debate: COVID-19 and Celiac Disease." International Journal of Celiac Disease 9, no. 1 (2021): 3-5.
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[1]  Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497-506.
In article      View Article
 
[2]  World Health Organization. Coronavirus disease (COVID-19) outbreak (http://www.who.int).
In article      
 
[3]  Zhuong NS, Zheng BJ, Li YM, et al. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People’s Republic of China, in February 2003. Lancet 2003; 363: 1353-1358.
In article      View Article
 
[4]  Ksiazek TG, Erdman D, Goldsmith CD, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 2003; 348: 1953-1966.
In article      View Article  PubMed
 
[5]  Drosten C, Gunther S, Preiser W, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003; 348: 1967-1976.
In article      View Article  PubMed
 
[6]  Zaki AM, van Boheemen S, Bestebroer TM, et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012; 367: 1814-1820.
In article      View Article  PubMed
 
[7]  Meng X, Lou Q-y, Yang W-y, et al. Gordian knot: gastrointestinal lesions caused by three pathogenic coronaviruses from SARS-CoV and MERS-CoV to SARS-CoV-2. Europ J Pharmacol 2021; 890: 173659.
In article      View Article  PubMed
 
[8]  Freeman HJ. COVID-19 diarrhea. Int J Celiac Disease 2020; 8: 60-63.
In article      
 
[9]  Lerner A. Covid-19 and the human gut: a new runner on the tract. Int J Celiac Disease 2020; 8: 64-67
In article      
 
[10]  Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; 382: 929-936.
In article      View Article  PubMed
 
[11]  Xiao F, Tang M, Zheng X, et al. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 2020; 158:1831-1833.
In article      View Article  PubMed
 
[12]  Zhou P, Yang L, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579: 270-273.
In article      View Article  PubMed
 
[13]  Harmer D, Gilbert M , Borman R, et al. Quantitative mRNA expression profiling of ACE2, a novel homologue of angiotensin covering enzyme. FEBS Lett 2002; 532: 107-110.
In article      View Article
 
[14]  Yan R, Zhang Y, Li Y, et al. Structural basis for the recognition of SARS-Cov-2 by full length human ACE2. Science 2020; 367: 1444-1448.
In article      View Article  PubMed
 
[15]  Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; In press.
In article      View Article  PubMed
 
[16]  Gu J, Han B, Wang J. COVID-19: gastrointestinal manifestations and potential fecal-oral transmission. Gastroenterology 2020; 158: 1518-1519.
In article      View Article  PubMed
 
[17]  Hashimoto T, Perlot T, Rehman A, et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 2012; 487: 477-481.
In article      View Article  PubMed
 
[18]  Monteleone G, Ardizzone S. Are patients with inflammatory bowel disease at increased risk for Covid-19 infection? J Crohn’s and Colitis 2020; 14: 1334-1336.
In article      
 
[19]  Meghool F, Valiani A, Safari T, et al. Gastrointestinal and renal complications in SARS-CoV-2 infected patients: role of immune system. Scans J Immunol 2020; 00: e12999.
In article      View Article  PubMed
 
[20]  Burgueno JF, Reich A, Hazime H, et al. Expression of SARS-CoV-2 entry molecules ACE2 and TMRSS2 in the gut of patients with IBD. Inflammatory Bowel Dis 2020; 26: 797-808.
In article      View Article  PubMed
 
[21]  Neurath MF. COVID-19 and immunomodulation in IBD. Gut 2020: 69: 1335-1342.
In article      View Article  PubMed
 
[22]  Emmi G, Bettiol A, Mattioni I, et al. SARS-CoV-2 infection among patients with systemic autoimmune disease. Autoimmunity Rev 2020; 19: 102575.
In article      View Article  PubMed
 
[23]  Marild K, Fredlund H, Ludvigsson JF. Increased risk of hospital admission for influenza in patients with celiac disease: a nationwide cohort study in Sweden. Am J Gastroenterol 2010; 105: 2465-2473.
In article      View Article  PubMed
 
[24]  Zingone F, Abdul Sultan A, Crooks CJ, et al. The risk of community-acquired pneumonia among 9803 patients with celiac disease compared to the general population: a cohort study. Aliment Pharmacol There 2016; 44: 57-67.
In article      View Article  PubMed
 
[25]  Canova C, Ludvigsson J, Baldo V, et al. Risk of bacterial pneumonia and pneumococcal infection in youths with celiac disease—a population-based study. Dig Liver Dis 2019; 51: 1101-1105.
In article      View Article  PubMed
 
[26]  Zingone F, D’Odorico A, Lorenzon G, et al. Risk of COVID-19 in celiac disease patients. Autoimmunity Rev 2020; 19: 102639.
In article      View Article  PubMed
 
[27]  Gokden Y, Hot S, Adas M, et al. Celiac disease and COVID-19 pandemic: should we worry? Acta Gastroenterol Belg 2020; 83: 517-525.
In article      
 
[28]  Monzani A, Lionetti E, Felici E, et al. Adherence to the gluten-free diet during the lockdown for COVID-19 pandemic: a web-based survey of Italian subjects with celiac disease. Nutrients 2020; 12: 3467.
In article      View Article  PubMed
 
[29]  Siniscalchi M, Singole G, Savarino EV, et al. COVID-19 pandemic perception in adults with celiac disease: an impulse to implement the use of telemedicine. Dig Liver Dis 2020; 52: 1071-1075.
In article      View Article  PubMed
 
[30]  Catassi GN, Vallorani M, Cerloni F, et al. A negative fallout of COVID-19 lockdown in Italy: life-threatening delay in the diagnosis of celiac disease. Dig Liver Dis 2020; 52: 1092-1093.
In article      View Article  PubMed
 
[31]  Schiepatti A, Alimenti E, Naimaris S, et al. Prevalence, incidence and clinical features of SARS-CoV-2 infection in adult celiac patients. Eur J Gastroenterol Hepatol 2021; In press.
In article      View Article  PubMed
 
[32]  Elli L, Scaramella L, Lombardo V, et al. Refractory celiac disease and COVID-19 outbreak: findings from a high incidence scenario in Northern Italy. Clin Res Hepatol Gastroenterol 2020; 44: e115-e120.
In article      View Article  PubMed
 
[33]  Freeman HJ. Biopsy-defined adult celiac disease and selective immunoglobulin A deficiency. Int J Celiac Disease 2017; 5: 10-13.
In article      
 
[34]  Naito Y, Takagi T, Yamamoto T, et al. Association between selective IgA deficiency and COVID-19. J Clin Biochem Nutr 2020; 67: 122-125.
In article      View Article  PubMed