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COVID-19 IN INFLAMMATORY BOWEL DISEASE: SHOULD WE BE MORE CAREFUL WITH THE USE OF SALICYLATES?

COVID-19 na doença inflamatória intestinal: devemos ser mais cautelosos com o uso dos salicilatos?

ABSTRACT

Backgrounds:

Fortunately, much has been studied about COVID-19 in patients with inflammatory bowel diseases (IBD). Evidence suggests that these patients do not appear to be at increased risk of severe COVID-19. However, there are still some uncertainties regarding the clinical manifestations of COVID-19 in patients with immune-mediated diseases.

Objective:

This study aimed to describe the main symptoms of COVID-19 and their frequency in IBD patients and evaluate the impact of the IBD therapeutic drugs on clinical presentation of COVID-19 and to determine factors associated with COVID-19 in this population.

Methods:

Adult patients with IBD from three tertiary-care public, teaching hospitals in Ceará, Northeastern Brazil, were evaluated during one scheduled appointment from March to December 2020. Patients with possible or confirmed COVID-19 were compared with patients without COVID-19. Furthermore, incidences of each symptom were evaluated based on the use of IBD therapeutic drugs.

Results:

A total of 515 patients with IBD were included in the study: 234 with CD, and 281 with UC. Of these, 174 patients (34%) had possible/confirmed COVID-19 of whom 156 (90%) were symptomatic. Main symptoms were fever (65%) and headache (65%); gastrointestinal symptoms occurred in one third of patients and were higher than COVID-19 in general population. The factors associated with having COVID-19 were female gender (OR 1.71, 95%CI: 1.17-2.50); contact at home (OR 5.07, 95%CI: 3.31-7.78) and outside the home (OR 3.14, 95%CI: 2.10-4.71) with a case of COVID-19; work outside of the home (OR 1.87, 95%CI: 1.26-2.78); family history of COVID-19 (OR 2.29, 95%CI 1.58-3.33) use of salicylate (OR 1.71, 95%CI: 1.17-4.28); and asthma (OR 7.10, 95%CI: 1.46-34.57).

Conclusion:

IBD patients at high risk of COVID-19 infection may need to avoid salicylate therapy but further studies are necessary to confirm this association.

Keywords:
Inflammatory bowel disease; COVID-19; salicylates

RESUMO

Contexto:

Felizmente, muito se tem estudado sobre a COVID-19 em pacientes com doenças inflamatórias intestinais (DII). As evidências sugerem que esses pacientes não parecem ter risco aumentado de COVID-19 grave. Mas ainda se tem algumas incertezas com relação às manifestações clínicas da COVID-19 em portadores de doenças imunomediadas.

Objetivo:

Este estudo teve como objetivo descrever os principais sintomas da COVID-19 e sua frequência em pacientes com DII e avaliar o impacto dos medicamentos utilizados no tratamento das DII na apresentação clínica da COVID-19.

Métodos:

Pacientes adultos com DII de três hospitais públicos terciários de ensino do Ceará, Nordeste do Brasil, foram avaliados em consulta ambulatorial no período de março a dezembro de 2020. Pacientes com COVID-19 possível ou confirmada foram comparados com pacientes sem COVID-19. Além disso, as incidências de cada sintoma foram avaliadas com base no uso de medicamentos utilizados para tratamento da DII.

Resultados:

Foram incluídos no estudo 515 pacientes com DII: 234 com DC e 281 com RCU. Destes, 174 pacientes (34%) tinham COVID-19 possível/confirmado, dos quais 156 (90%) eram sintomáticos. Os principais sintomas foram febre (65%) e dor de cabeça (65%); sintomas gastrointestinais ocorreram em um terço dos pacientes, sendo mais frequentes do que na população geral com COVID-19. Os fatores associados a ter COVID-19 foram sexo feminino (OR 1,71, IC95%: 1,17-2,50); ter contato com caso de COVID-19, tanto intradomiciliar (OR 5,07; IC95%: 3,31-7,78) como fora do domicílio (OR 3,14; IC95%: 2,10-4,71); trabalhar fora de casa (OR 1,87; IC95%: 1,26-2,78); história familiar de COVID-19 (OR 2,29, IC95% 1,58-3,33), uso de salicilato (OR 1,71, IC95%: 1,17-4,28) e asma (OR 7,10; IC95%: 1,46-34,57).

Conclusão:

Pacientes com DII com alto risco de infecção por COVID-19 podem precisar evitar a terapia com salicilatos, mas mais estudos são necessários para confirmar esta associação.

Palavras-chave:
Doença inflamatória intestinal; COVID-19; salicilatos

HIGHLIGHTS

•Most inflammatory bowel diseases and COVID-19 patients were symptomatic, and fever was the main symptom.

•Patients with inflammatory bowel diseases and COVID-19 had more gastrointestinal symptoms than the general population with COVID-19.

•Use of salicylates, female gender and asthma were associated with COVID-19.

•Use of immunosuppressants or immunobiological drugs did not alter the clinical presentation of COVID-19.

INTRODUCTION

COVID-19 is the disease caused by the SARS-CoV-2, a coronavirus first reported in December 2019, which quickly spread to several countries and was declared a pandemic11. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.. The most common symptoms are fever, cough, dyspnea, myalgia, fatigue, chest tightness, headache, hemoptysis, and diarrhea22. Pegado R, Silva-Filho E, Lima INDF, Gualdi L. Coronavirus disease 2019 (COVID-19) in Brasil: information to physical therapists. Rev Assoc Med Bras. 2020;66:498-501.. Until March 2023, more than 700 million confirmed cases had been reported worldwide (with more than 37 million cases in Brazil), with a total death count of over 6 million33. World Health Organization (WHO). WHO COVID-19 Dashboard. Geneva: World Health Organization, 2020. Available from: https://covid19.who.int/
https://covid19.who.int/...
. In Ceará (a state in the Brazilian Northeast), almost 1.5 million cases of COVID-19 were confirmed, with more than 28,000 deaths44. Secretary of Health of the State of Ceará (SESA). COVID-19 bulletins. 2023. Available from: https://www.saude.ce.gov.br/download/covid-19
https://www.saude.ce.gov.br/download/cov...
.

As the pandemic expanded, concern on the impact of COVID-19 on immunosuppressed patients, such as those with inflammatory bowel diseases (IBD) grew. IBD includes Crohn’s disease (CD) and ulcerative colitis (UC) that are chronic, immune-mediated diseases, whose pathogenesis involves a complex interaction between environmental factors and genetic susceptibility55. Zhang YZ, Li YY. Inflammatory bowel disease: pathogenesis. World J Gastroenterol. 2014;20:91-9.. Symptoms of IBD are heterogeneous and may include symptoms related to the gastrointestinal tract and also systemic symptoms66. Gomollón F, Dignass A, Annese V, Tilg H, Van Assche G, Lindsay JO, et al; ECCO. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical Management. J Crohns Colitis. 2017;11:3-25.. Study from a reference center located in Brazil77. Nóbrega VG, Silva INN, Brito BS, Silva J, Silva MCMD, Santana GO. The onset of Clinical Manifestations in Inflammatory Bowel Disease Patients. Arq Gastroenterol. 2018;55:290-5., showed that the main clinical manifestations of IBD patients were weight loss, followed by diarrhea, abdominal pain, fecal urgency, asthenia and blood in the stool.

Most IBD patients are currently exposed to immunosuppressive drugs, including corticosteroids, immunomodulators, and immunobiologicals for prolonged periods which can increase the risk of infection88. Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, et al; IBD guidelines e Delphi consensus group. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019;68(Suppl 3):s1-s106.,99. Monteleone G, Ardizzone S. Are Patients with Inflammatory Bowel Disease at Increased Risk for Covid-19 Infection? J Crohns Colitis. 2020;14:1334-6.. These drugs have been associated with higher rates of serious viral and bacterial infections1010. Ma C, Lee JK, Mitra AR, Teriaky A, Choudhary D, Nguyen TM, et al. Systematic review with meta-analysis: efficacy and safety of oral Janus kinase inhibitors for inflammatory bowel disease. Aliment Pharmacol Ther. 2019;50:5-23..

Little is known about the impact of COVID-19 on patients with chronic inflammatory diseases such as IBD, particularly those requiring the use of systemic immunosuppressant drugs. Older age, increased number of comorbidities, and the use of systemic corticosteroid are risk factors for adverse COVID-19 outcomes in patients with IBD. However, TNF-antagonist therapy does not seem to be associated with severe COVID-191111. Brenner EJ, Ungaro RC, Gearry RB, Kaplan GG, Kissous-Hunt M, Lewis JD, et al. Corticosteroids, But Not TNF Antagonists, Are Associated With Adverse COVID-19 Outcomes in Patients With Inflammatory Bowel Diseases: Results From an International Registry. Gastroenterology. 2020;159:481-491.e3..

COVID-19 can cause gastrointestinal (GI) symptoms. A meta-analysis suggested that up to 17.6% of COVID-19 patients have these symptoms1212. Cheung KS, Hung IFN, Chan PPY, Lung KC, Tso E, Liu R, et al. Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples From a Hong Kong Cohort: Systematic Review and Meta-analysis. Gastroenterology. 2020;159:81-95.. Data are conflicting with some reports suggesting worse prognosis among those with GI symptoms while others found better outcomes1313. Livanos AE, Jha D, Cossarini F, Gonzalez-Reiche AS, Tokuyama M, Aydillo T, et al. Intestinal Host Response to SARS-CoV-2 Infection and COVID-19 Outcomes in Patients With Gastrointestinal Symptoms. Gastroenterology. 2021;160:2435-2450.e34.. There are limited data on COVID-19 and GI symptoms among IBD patients.

The aims of this study were to describe the main symptoms of COVID-19 in IBD patients, including the frequency of GI symptoms during COVID; to evaluate the impact of immunosuppressants and immunobiological drugs on clinical presentation of COVID-19; and to determine factors associated with COVID-19 in this population.

METHODS

Setting and patients

Adult patients with IBD from three tertiary-care, public, teaching hospitals, reference centers for IBD in Ceará, Brazil were evaluated.

Study design and data collection

This is a retrospective study. Patients with IBD were evaluated during one scheduled appointment from March to December 2020. Their clinical and epidemiological data including associated factors and COVID-19 presentation and outcomes, as well as data on their underlying disease and its treatment were collected. In this cross-sectional design, the patient assessment was made by in-person care, after the application of an informed consent.

During the appointment, the attending gastroenterologists obtained data from the patients’ medical records and data collected from the patients’ interviews. Patients were evaluated for socio-demographic, and epidemiological data, underlying diseases, information on IBD, such as extension and severity, hospitalization for reasons other than COVID-19, and procedures undergone during the COVID-19 pandemic, laboratory data (including PCR for SARS-CoV-2 or serological result), and treatment of IBD. We considered the following drugs used during the pandemic to be immunosuppressants: thiopurines (azathioprine), methotrexate, calcineurin inhibitors (cyclosporine), and mycophenolate. Immunobiological drugs were: infliximab, adalimumab, golimumab, certolizumab, vedolizumab and ustekinumab. The COVID-19 pandemic period was established as starting on 1 March 2020 until the date of completion of the questionnaire. Physical activity was considered to be regular when performed more than three times a week. Family history of COVID-19 was established if a consanguineous relative had COVID-19. Exposure to COVID-19 at home was defined as living with any person who had become ill with COVID-19. Only mask use outside of the home was considered. The evaluation of the impact of COVID-19 on IBD was based on the patients’ perception (symptoms improved, worsened, or unchanged during/after COVID-19).

The extent of UC was evaluated according to the Montreal classification1414. Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005;19(Suppl A):5-36.: rectitis (disease limited to the rectum), left colitis (involvement up to the splenic flexure of the colon), and extensive colitis (involvement proximal to the splenic flexure). The behavior (phenotype) of CD was classified according to Montreal Classification1414. Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005;19(Suppl A):5-36.: non-stricturing non-penetrating disease (B1), stricturing disease (B2) and penetrating disease (B3). UC activity was evaluated using the partial Mayo score1515. Lewis JD, Chuai S, Nessel L, Lichtenstein GR, Aberra FN, Ellenberg JH. Use of the noninvasive components of the Mayo score to assess clinical response in ulcerative colitis. Inflamm Bowel Dis. 2008;14:1660-6. doi: 10.1002/ibd.20520.
https://doi.org/10.1002/ibd.20520...
≥2 and CD activity was evaluated using the Harvey-Bradshaw Index1616. Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity. Lancet. 1980;1:514. doi: 10.1016/s0140-6736(80)92767-1.
https://doi.org/10.1016/s0140-6736(80)92...
(HBI) ≥5.

Data analysis

For the analyses, the following definitions were used:

  • Possible COVID-19: symptoms compatible with COVID-19 (fever, nasal obstruction, sore throat, cough, dyspnea, headache, diarrhea, nausea or vomiting, anosmia, ageusia, and fatigue) during the period of the pandemic, plus the patient was untested for SARS-CoV-2 infection.

  • Confirmed COVID-19: symptomatic or asymptomatic patient with positive PCR for SARS-CoV-2 or positive serological result (the study was carried out in the pre-vaccination period).

  • Without COVID-19: tested negative or untested asymptomatic patient.

We compared data between the groups of patients with COVID-19 (possible or confirmed) and without. We also compared the frequency of each symptom of COVID-19 in the group of patients using immunosuppressants and/or immunobiological drugs with the group that did not use these drugs. For these comparisons, we used Fisher’s exact test. Variables that presented a P value <0.2 in the bivariate analysis were included in the multivariate analysis done using stepwise logistic regression.

Ethical issues

This study was approved by the ethics committee of the hospitals involved. There are no conflicts of interest between the authors and the objectives of this study.

RESULTS

A total of 515 patients with IBD were included: 234 with CD, and 281 with UC (Table 1). Most patients were in their 4th decade of life and were female. Median number of years of formal education was 14. Most had been vaccinated against influenza in 2020. Sixteen percent (n=84/515) engaged in regular physical activity. The most frequent comorbidity in addition to IBD, was hypertension, followed by diabetes mellitus. The most frequent means of transportation were car (31%); public transport (27%); and motorcycle (25%). Ninety-four percent reported that they always used a mask outside of the home. Exposure to COVID-19 cases at home and outside home occurred in 25% and 29%, respectively; 28% worked outside the home during the pandemic. Family cases of COVID-19 were reported by 47%. The mean time since the diagnosis of IBD was approximately 9 years. Salicylates were the most frequent drugs in use, followed by immunobiological drugs, and immunosuppressants.

Among the CD patients, 80% were considered to be in remission. Among the UC patients, 60% were in remission, and 28% (80/281) had mild disease. During pandemic, 235 procedures were undergone, mostly endoscopic (71%). A total of 49 hospital admissions for reasons other than COVID-19 were recorded during the pandemic, 63% due to IBD activity. The location of IBD can be seen in Table 1.

TABLE 1
Characteristics of 515 patients with IBD evaluated during the COVID-19 pandemic (March-December 2020).

One hundred and seventy-four patients (34%) had possible or confirmed COVID-19. Of the 68 confirmed, 74% had only a positive serology, 19% had only a positive PCR, and 7% had both tests positive. Among the confirmed cases, 74% had been symptomatic.

Considering only the 156 symptomatic patients, (confirmed or possible), most did not discontinue their medication for IBD during symptoms (77%), and 72% reported that COVID-19 had no impact on their IBD. Of patients with COVID-19, 2 (1.15%) required hospitalization.

Among the 156 symptomatic patients the main symptoms were: fever (65%), and headache (65%), with a median duration of 3 days and 4 days, respectively. Anosmia (63%), ageusia (60%), and fatigue (53%) were also frequent. GI symptoms were diarrhea (33%), and nausea/vomiting (19%), with a median duration of 3 days. There was no difference in clinical presentation of COVID-19 in patients who used immunosuppressants or immunobiological drugs except for less frequent nasal obstruction (SUPPLEMENTARY TABLE S1).

SUPPLEMENTARY TABLE S1.
Frequency of symptoms of COVID-19 in patients with inflammatory bowel diseases distributed according to the use of immunosuppressant and immunobiological drugs (March-December 2020).

In the bivariate analysis, the following factors were associated with having COVID-19 (possible or confirmed): female sex, contact with a case of COVID-19 at home; contact with a case of COVID-19 outside of the home; working outside of the home; having a family history of COVID-19; using a salicylate; and asthma. These variables remained significant in the multivariate analysis (Table 2).

TABLE 2
Factors associated with acquiring COVID-19 among 515 patients with IBD (March-December 2020).

CD was not associated with a higher risk of COVID-19 when compared to UC. Active disease, use of immunosuppressants, immunobiological, and corticosteroids did not increase the risk of having COVID-19.

Only two patients required hospitalization for COVID-19. Neither required intensive care. Both had CD, one was using corticosteroid and an immunobiological drug (vedolizumab), and during COVID-19 the use of the steroid was suspended, and the next dose of vedolizumab was postponed. The other was using salicylate and corticosteroid during COVID-19 and did not stop these medications.

DISCUSSION

Among 515 patients with IBD treated at tertiary-care centers in Ceará, Brazil, the prevalence infection caused by SARS-CoV-2 was 34% of which 90% were symptomatic. The most frequent symptoms of COVID-19 were fever and headache, and GI symptoms occurred in at least one third of patients (diarrhea, and nausea/vomiting). The use of immunosuppressants or immunobiologicals drugs did not change the clinical presentation of COVID-19. Factors associated with COVID-19 were female sex, contact with a case of COVID-19 at home; contact with a case of COVID-19 outside of the home; working outside home; having a family history of COVID-19; and asthma. Activity of IBD and type of treatment of IBD did not increase the risk of having COVID-19, except for the use of a salicylate which was associated with COVID-19, independently of age.

We found that patients with IBD and COVID-19 had a clinical presentation similar to the general population, as previously described, except for a higher frequency of GI symptoms such as diarrhea (33%) and nausea/vomiting (19%)1717. Stokes EK, Zambrano LD, Anderson KN, Marder EP, Raz KM, El Burai Felix S, et al. Coronavirus Disease 2019 Case Surveillance - United States, January 22-May 30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:759-65.. In the general population with COVID-19 these GI symptoms were reported to be around 10%1212. Cheung KS, Hung IFN, Chan PPY, Lung KC, Tso E, Liu R, et al. Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples From a Hong Kong Cohort: Systematic Review and Meta-analysis. Gastroenterology. 2020;159:81-95.,1818. Singh S, Khan A, Chowdhry M, Bilal M, Kochhar GS, Clarke K. Risk of Severe Coronavirus Disease 2019 in Patients With Inflammatory Bowel Disease in the United States: A Multicenter Research Network Study. Gastroenterology. 2020;159:1575-1578.e4.,1919. Jin X, Lian J-S, Hu J-H, Gao J, Zheng L, Zhang YM, et al. Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut. 2020;69:1002-9.. The greater presence of GI symptoms in IBD patients with COVID-19 has been described previously but was less frequent than in our patients2020. Ungaro RC, Brenner EJ, Gearry RB, Kaplan GG, Kissous-Hunt M, Lewis JD, et al. Effect of IBD medications on COVID-19 outcomes: results from an international registry. Gut 2021;70:725-32.

21. D’Amico F, Rahier JF, Leone S, Peyrin-Biroulet L, Danese S. Views of patients with inflammatory bowel disease on the COVID-19 pandemic: a global survey. Lancet Gastroenterol Hepatol. 2020;5:631-2.
-2222. Singh AK, Jena A, Kumar-M P, Jha DK, Sharma V. Clinical presentation of COVID-19 in patients with inflammatory bowel disease: a systematic review and meta-analysis. Intest Res. 2022;20:134-43.. Our study showed that the main COVID-19 GI symptom in patients with IBD is diarrhea, present in about a third of patients. This is important as GI symptoms may be erroneously interpreted as a flare of IBD. Activity of IBD was not associated with having COVID-19. The clinical presentation of COVID-19 was not affected by immunosuppressants or immunobiologicals. Transplanted immunosuppressed patients have experienced a different clinical presentation of COVID-19, with more dyspnea and myalgia and a lower frequency of fever, but contrary to these other immunosuppressed patients, in IBD patients, the use of immunosuppressant and immunobiologicals does not seem to affect the clinical manifestations of COVID-192323. Cravedi P, Mothi SS, Azzi Y, Haverly M, Farouk SS, Pérez-Sáez MJ, et al. COVID-19 and kidney transplantation: Results from the TANGO International Transplant Consortium. Am J Transplant. 2020;20:3140-8.,2424. Guillen E, Pineiro GJ, Revuelta I, Rodriguez D, Bodro M, Moreno A, et al. Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation? Am J Transplant. 2020;20:1875-8.. Studies and meta-analyses about COVID-19 in patients with IBD were performed, but they did not study correlation among symptoms and the use of immunosuppressants and immunobiologicals2222. Singh AK, Jena A, Kumar-M P, Jha DK, Sharma V. Clinical presentation of COVID-19 in patients with inflammatory bowel disease: a systematic review and meta-analysis. Intest Res. 2022;20:134-43.,2525. Salvatori S, Baldassarre F, Mossa M, Monteleone G. Long COVID in Inflammatory Bowel Diseases. J Clin Med. 2021;10:5575.. In the state of Ceará, where the study was carried out, until March 2023, 0.64% of population with COVID-19 required hospitalization (9,384 hospitalizations among 1,451,847 cases). Among our 174 SARS-CoV-2-infected IBD patients, 2 (1.15%) required hospitalization. Although our numbers are too small to draw conclusions, it may suggest that these patients are at higher risk of severe COVID-19. More studies are necessary to clarify this issue.

Although in our IBD patients, females were more frequent, we found that being female was independently associated with COVID-19, unlike the general population where COVID-19 affected men and women equally2626. Mukherjee S, Pahan K. Is COVID-19 Gender-sensitive? J Neuroimmune Pharmacol. 2021;16:38-47.. We also found an association between asthma and COVID-19, which is in line with recently published studies associating asthma with severe forms of COVID-192727. Chiner-Vives E, Cordovilla-Pérez R, de la Rosa-Carrillo D, García-Clemente M, Izquierdo-Alonso JL, Otero-Candelera R, et al. Short and Long-Term Impact of COVID-19 Infection on Previous Respiratory Diseases. Arch Bronconeumol. 2022;58(Suppl 1):39-50.. Other factors associated with COVID-19 were contact with COVID-19 cases (at home and outside, and in the family), working outside the home, and the use of salicylates. Use of immunosuppressants, immunobiological, and corticosteroids were not associated with COVID-19, and there was no higher hospitalization rate in this group, findings consistent with other studies2020. Ungaro RC, Brenner EJ, Gearry RB, Kaplan GG, Kissous-Hunt M, Lewis JD, et al. Effect of IBD medications on COVID-19 outcomes: results from an international registry. Gut 2021;70:725-32.,2828. Al-Ani AH, Prentice RE, Rentsch CA, Johnson D, Ardalan Z, Heerasing N, et al. Review article: prevention, diagnosis and management of COVID-19 in the IBD patient. Aliment Pharmacol Ther. 2020;52:54-72.,2929. Lee MH, Li HJ, Wasuwanich P, Kim SE, Kim JY, Jeong GH, et al. COVID-19 susceptibility and clinical outcomes in inflammatory bowel disease: An updated systematic review and meta-analysis. Rev Med Virol. 2023;33:e2414..

The association between salicylates and COVID-19 is controversial. Studies that found this association were prone to selection bias. Salicylates have a better safety profile and are preferred in elderly patients who also have a higher risk for COVID-192020. Ungaro RC, Brenner EJ, Gearry RB, Kaplan GG, Kissous-Hunt M, Lewis JD, et al. Effect of IBD medications on COVID-19 outcomes: results from an international registry. Gut 2021;70:725-32.,2222. Singh AK, Jena A, Kumar-M P, Jha DK, Sharma V. Clinical presentation of COVID-19 in patients with inflammatory bowel disease: a systematic review and meta-analysis. Intest Res. 2022;20:134-43.,3030. Attauabi M, Seidelin J, Burisch J; Danish COVID-IBD Study Group. Association between 5-aminosalicylates in patients with IBD and risk of severe COVID-19: an artefactual result of research methodology? Gut. 2021;70:2020-2.. Our study, however, included a young population, with a mean age of 45 years. In order to evaluate the influence of age we performed a multivariate analysis that included the variable age and observed that the association between the use of salicylate and COVID-19 was independent.

Also, we adjusted for factors such as sex, comorbidities (hypertension, asthma and hypothyroidism), activity disease, and type of IBD and the association of salicylates and COVID-19 remained. Similar to corticosteroids, salicylate may impair the initial immune response to COVID-19, leading to adverse outcomes3131. Stevens C, Lipman M, Fabry S, Moscovitch-Lopatin M, Almawi W, Keresztes S, et al. 5-Aminosalicylic acid abrogates T-cell proliferation by blocking interleukin-2 production in peripheral blood mononuclear cells. J Pharmacol Exp Ther. 1995;272:399-406.. Furthermore, some studies have shown that the use of immunosuppressants for patients with IBD helps to suppress COVID-19 activity, avoiding cytokine storm, and acting as a protective factor3232. Hormati A, Ghadir MR, Zamani F, Khodadadi J, Khodadust F, Afifian M, et al. Are there any association between COVID‐19 severity and immunosuppressive therapy? Immunol Lett. 2020;224:12‐13.,3333. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033-4..

Although some comorbidities (diabetes mellitus, hypertension, chronic kidney disease, obesity, and cancer) are associated with worse COVID-19 outcomes, we found no association between hypertension, diabetes and COVID-193434. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW. et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020;323:2052-9. doi: 10.1001/jama.2020.6775. Erratum in: JAMA. 2020;323:2098.
https://doi.org/10.1001/jama.2020.6775...
. Most of our patients reported that COVID-19 had no impact on the activity of IBD, contrary to a study carried out by Salvatori S et al. that showed that 81% of patients had IBD exacerbation after SARS-CoV-2 infection2525. Salvatori S, Baldassarre F, Mossa M, Monteleone G. Long COVID in Inflammatory Bowel Diseases. J Clin Med. 2021;10:5575..

Our study has limitations. It is a retrospective study with data collection based on the information given by the patients. We assumed that patients with respiratory symptoms in the critical period of the pandemic (lockdown period) had COVID-19, since we still did not have tests widely available at that time. Unfortunately, we were unable to assess COVID-19-related mortality, as data were collected at the outpatient clinic after resolution of the infection.

CONCLUSION

In conclusion, the clinical presentation of COVID-19 in patients with IBD was not affected by immunosuppressants and immunobiologicals, and was similar to that of the general population, however, GI manifestations, mainly diarrhea, seemed to be more common. This is important so that health professionals and patients can know what to expect from COVID-19 in IBD patients avoiding confusion with an IBD flare. Female gender was independently associated with COVID-19, as was the use of salicylates. Immunosuppressants, immunobiologicals and corticosteroids did not influence the risk of COVID-19. IBD patients at high risk for SARS-CoV-2 infection may need to avoid salicylate therapy, but further studies are necessary to confirm this association.

ACKNOWLEDGMENTS

The authors would like to acknowledge all healthcare and patients for participating in this study.

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  • Disclosure of funding: none
  • Declaration of use of artificial intelligence: none

Publication Dates

  • Publication in this collection
    17 June 2024
  • Date of issue
    2024

History

  • Received
    09 Nov 2023
  • Accepted
    26 Mar 2024
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