No Durable Impact of COVID-19 on Intestinal Disease Activity in Subjects With IBD
Authors: Dana J. Lukin, Gabriela Funez-dePagnier, Svetlana Lima, Daniel Lai, Lucia Duenas-Bianchi, Waseem Ahmed, Vinita Jacob, Robert Battat, Ellen Scherl, Randy S. Longman
Journal: Clinical Gastroenterology and Hepatology (2021)

What You Need to KnowBackgroundAlthough patients with inflammatory bowel disease reported an increased frequency of gastrointestinal symptoms following infection, the durable impact of COVID-19 on IBD activity and the microbiome is not well defined.FindingsLongitudinal follow-up data over 6 months revealed no durable impact of COVID-19 on clinical IBD disease activity or microbiome composition.Implication for patient careWhile validation in additional cohorts is required, these data reassuringly suggest no long-term impact of COVID-19 on IBD disease activity and support guidelines for continued IBD maintenance care during the pandemic. Although patients with inflammatory bowel disease reported an increased frequency of gastrointestinal symptoms following infection, the durable impact of COVID-19 on IBD activity and the microbiome is not well defined. Longitudinal follow-up data over 6 months revealed no durable impact of COVID-19 on clinical IBD disease activity or microbiome composition. While validation in additional cohorts is required, these data reassuringly suggest no long-term impact of COVID-19 on IBD disease activity and support guidelines for continued IBD maintenance care during the pandemic. Although patients with inflammatory bowel disease (IBD) reported an increased frequency of gastrointestinal (GI) symptoms following infection,1Lukin D.J. Kumar A. Hajifathalian K. et al.Baseline disease activity and steroid therapy stratify risk of COVID-19 in patients with inflammatory bowel disease.Gastroenterology. 2020; 159: 1541-1544Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar,2Brenner E.J. Ungaro R.C. Gearry R.B. 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: 481-491Abstract Full Text Full Text PDF PubMed Scopus (565) Google Scholar the durable impact of COVID-19 on IBD activity and the microbiome is not well defined. Our study aims were to compare clinical, endoscopic, and laboratory markers of disease activity and the fecal microbiome in IBD participants 6 months pre- and post-COVID-19. Using an established longitudinal cohort, we identified 118 IBD patients with COVID-19 infection (Supplementary Table 1). Clinical characteristics and disease activity were assessed up to 6 months before COVID-19, during COVID-19 (defined as 1–30 days postinfection), and up to 6 months after. Active disease was defined by a Harvey Bradshaw Index >4, Mayo Score ≥2, Simple Endoscopic Score-Crohn's Disease ≥2, or Mayo Endoscopic Score ≥1. 16S rRNA sequencing of V4 and V5 regions was analyzed using USEARCH and RDP database to generate OTU tables (Supplementary Methods). Although upper respiratory and new GI symptoms were common in patients with IBD (Supplementary Table 1), there were no significant changes in IBD clinical disease activity, endoscopic evaluation, or laboratory markers up to 7 months post-COVID-19 compared with the most recent evaluation up to 6 months before infection (Table 1). Active disease was present in 60% of the cohort before COVID-19 and 55% and 59% during and post-COVID-19, respectively.Table 1Clinical, Endoscopic, and Laboratory Markers Pre-, During, and Post-COVID-19VariablesPre-COVID-180 to -1 dCOVID0 to +30 dPost-COVID+31 to +210 dP valuePre vs PostClinical DAI, Avg (n).7397HBI4.7 (50)4.7 (21)4.9 (41).74PMS3.0 (25)4.8 (6)2.1 (19).24Endoscopic DAI, Avg (n)SES-CD7.2 (17)7 (1)8.9 (15).69MES1.5 (9)2 (1)1.7 (11).70Biomarkers, Avg (n)C-reactive protein1.2 (83)2.5 (15)1.3 (56).18ESR25 (63)25 (14)26 (44).95Hemoglobin12.8 (84)12.6 (26)13.2 (60).50Fecal calprotectin388 (44)522 (12)250 (40).20Active disease, n (%)49 (60)16 (55)38 (59).87Delayed/discontinued9 (69)5 (83)4 (40)COVID-19 GI symptoms20 (61)8 (39)20 (71)Need for surgery, n (%)3 (2.8)0 (0)2 (1.8).68Need for IBD hospitalization, n (%)6 (5.6)2 (1.7)7 (6.2)> .99Medication change, n (%)53 (50)33 (28)45 (40).14Newly started42 (40)14 (12)36 (32)Steroid17 (16)4 (3.4)15 (13)Delayed2 (1.9)10 (8.5)5 (4.4)Discontinued20 (19)8 (6.8)15 (13)NOTE. Unpaired Mann-Whitney and paired Wilcoxon revealed no significant differences between pre- and post-COVID-19 clinical, endoscopic, and laboratory values. Fisher exact test was used to compare differences in patient number with active disease, need for surgery, hospitalization, or medication change.DAI, disease activity index; ESR, erythrocyte sedimentation rate; GI, gastrointestinal; HBI, Harvey Bradshaw Index; IBD, inflammatory bowel disease; MES, Mayo Endoscopic Score; PMS, partial Mayo score; SES-CD, Simple Endoscopic Score-Crohn's Disease. Open table in a new tab NOTE. Unpaired Mann-Whitney and paired Wilcoxon revealed no significant differences between pre- and post-COVID-19 clinical, endoscopic, and laboratory values. Fisher exact test was used to compare differences in patient number with active disease, need for surgery, hospitalization, or medication change. DAI, disease activity index; ESR, erythrocyte sedimentation rate; GI, gastrointestinal; HBI, Harvey Bradshaw Index; IBD, inflammatory bowel disease; MES, Mayo Endoscopic Score; PMS, partial Mayo score; SES-CD, Simple Endoscopic Score-Crohn's Disease. Ten patients in our cohort reported a delay in medical therapy and 8 discontinued IBD medications during COVID-19; however, this subset and the 43 participants reporting GI symptoms during COVID-19 had no significant change in disease activity (Table 1). There were no differences in the need for corticosteroids, a change in medical therapy, or IBD-related surgery or hospitalization during or post-COVID-19 compared with the prior 6 months. Preliminary studies in hospitalized patients with severe COVID-19 suggested the potential impact of infection on the microbiome.3Zuo T. Zhang F. Lui G.C.Y. et al.Alterations in gut microbiota of patients with COVID-19 during time of hospitalization.Gastroenterology. 2020; 159: 944-955Abstract Full Text Full Text PDF PubMed Scopus (1002) Google Scholar From a subset of 12 patients for whom fecal samples were available before COVID-19, 16S rRNA sequence was performed to assess the impact of infection on microbiome composition. Paired and unpaired analysis between pre- and post-COVID-19 samples revealed no significant difference in alpha diversity (Shannon index, Supplementary Figure 1A) or beta diversity (Bray-Curtis distance metric, Supplementary Figure 1B). Similar to previous results suggesting that IBD activity correlates with changes in the microbiome,4Gevers D. Kugathasan S. Denson L.A. et al.The treatment-naive microbiome in new-onset Crohn's disease.Cell Host Microbe. 2014; 15: 382-392Abstract Full Text Full Text PDF PubMed Scopus (2238) Google Scholar principal coordinate analysis of Bray-Curtis distance metric revealed that the microbiome of mild disease (Harvey Bradshaw Index 5–7 or Mayo 3–5) was distinct from moderate disease (Harvey Bradshaw Index 8–16 or Mayo 6–10; Supplementary Figure 1C); however, there was no significant change comparing pre- and post-COVID-19 samples (Supplementary Figure 1D). In contrast, individual participants over time remained distinct (PERMANOVA, Subject × Time; P = .04; Supplementary Figure 1E). Similarly, principal coordinate analysis revealed no significant differences when stratified by those affected by COVID-19-associated diarrhea (Supplementary Figure 1F). With the increased frequency of new GI symptoms associated with COVID-19 in patients with IBD, there was initial concern that infection may lead to durable negative effects on IBD activity. This concern was further compounded by the need to delay or discontinue immunosuppressive therapy in IBD patients with active COVID-19.5Rubin D.T. Feuerstein J.D. Wang A.Y. et al.AGA Clinical Practice Update on management of inflammatory bowel disease during the COVID-19 pandemic: expert commentary.Gastroenterology. 2020; 159: 350-357Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar Reassuringly, our data reveal no significant impact on disease activity during 6 months follow-up post-COVID-19. Although subjects profiled in this study were primarily managed as outpatients, most suffered from respiratory symptoms and about one-third with new-onset GI symptoms.1Lukin D.J. Kumar A. Hajifathalian K. et al.Baseline disease activity and steroid therapy stratify risk of COVID-19 in patients with inflammatory bowel disease.Gastroenterology. 2020; 159: 1541-1544Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar,2Brenner E.J. Ungaro R.C. Gearry R.B. 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: 481-491Abstract Full Text Full Text PDF PubMed Scopus (565) Google Scholar Given the limited number of subjects in this study with severe COVID-19, it is important to follow additional cases of severe COVID-19 in patients with IBD and to assess the impact of long-haul symptoms. Encouragingly, these results indicate no significant need for IBD-related surgery or hospitalization. Initial reports suggesting distinct changes in the microbiome of patients with severe COVID-19 raised the possibility that patients with IBD may be at higher risk for microbiome alterations, which could subsequently impact disease activity.3Zuo T. Zhang F. Lui G.C.Y. et al.Alterations in gut microbiota of patients with COVID-19 during time of hospitalization.Gastroenterology. 2020; 159: 944-955Abstract Full Text Full Text PDF PubMed Scopus (1002) Google Scholar Although our data show microbiome differences based on disease activity, we did not detect distinct changes in participants before and after COVID-19. Although validation in additional cohorts is required, our microbiome analysis reflects the first longitudinal analysis of the fecal microbiome before and after COVID-19. Moreover, these findings are consistent with more recent reports suggesting that microbiome changes seen in patients with severe COVID-19 may reflect antibiotic use as part of hospital care rather than COVID-19 severity.6Britton G.J. Chen-Liaw A. Cossarini F. et al.SARS-CoV-2-specific IgA and limited inflammatory cytokines are present in the stool of select patients with acute COVID-19.medRxiv. 2020; Google Scholar Collectively, these data reveal no durable impact of COVID-19 on clinical IBD disease activity or microbiome composition and provide data supporting the current guidelines for continued IBD maintenance care during the pandemic. IBD clinical disease activity (Harvey Bradshaw Index, partial Mayo score), endoscopic score, and laboratory markers (erythrocyte sedimentation rate, C-reactive protein, hemoglobin, fecal calprotectin) were assessed up to 6 months before COVID-19, during COVID-19 (defined as 1–30 days postinfection), and up to 6 months after. Values were compared using unpaired Mann-Whitney or paired Wilcoxon tests. The need for corticosteroids, a change in medical therapy, or IBD-related surgery/hospitalization during or post-COVID-19 was compared with the preceding 6 months. Values were compared using Fisher exact test. In a subset of 12 patients, 16S rRNA sequencing was performed as previous described and data were rarified at 10,000 reads per sample. Briefly, the 16S rRNA gene V4 and V5 regions were amplified as previously described (https://earthmicrobiome.org). Amplicons were then sequenced in an Illumina MiSeq platform using the 2 × 250 bp paired-end protocol. Read pairs were processed using USEARCH1Edgar R.C. Search and clustering orders of magnitude faster than BLAST.Bioinformatics. 2010; 26: 2460-2461Crossref PubMed Scopus (15579) Google Scholar and the RDP database2Cole J.R. Wang Q. Fish J.A. et al.Ribosomal Database Project: data and tools for high throughput rRNA analysis.Nucleic Acids Res. 2014; 42: D633-642Crossref PubMed Scopus (3082) Google Scholar to generate a rarefied OTU table. Alpha and beta diversity analyses were then performed at the OTU-level. Microbiome analysis was performed in R studio (Boston, MA). Alpha and beta diversity was calculated using R package "phyloseq,"3McMurdie P.J. Holmes S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data.PLoS One. 2013; 8e61217Crossref PubMed Scopus (10878) Google Scholar whereas plots were constructed in "ggplot2." Beta divergence based on Bray-Curtis dissimilarity was calculated using microbiome package in R studio. Bray-Curtis distance metric was used to evaluate microbiome composition before and after COVID-19 and Monte Carlo permutation test (PERMANOVA) was used to assess differences between centroids shown in the principal coordinate plots.Supplementary Table 1Clinical Characteristics and Comorbidities of COVID-19 IBD CohortVariableAll IBD (n = 118)Age, y, mean (SD)42.1 (16)Sex, n (%) Female63 (54) Male54 (46)IBD type Crohn's disease73 (62) Ulcerative colitis40 (34) Other colitis5 (4.2)Body mass index, kg/m2 average (SD)27 (6.8)Comorbidities, n (%) Obesity30 (25) Former smoker23 (20) Current smoker2 (1.7) Diabetes5 (4.3) CAD2 (1.7) Heart failure1 (0.9) Hypertension20 (17) Asthma8 (6.9) COPD0 (0) Cirrhosis1 (0.9) Chronic kidney disease1 (0.9Current medications, n (%) Any biologic65 (55) Anti-TNF23 (20) Vedolizumab22 (19) Ustekinumab20 (17) JAK inhibitors6 (5.1) Immunomodulator4 (3.4) Steroids19 (16) Prednisone8 (6.8) Budesonide11 (9.3) MesalaminesOral40 (34)Rectal25 (21) Hypertension medications17 (15)ACE-ARB medications7 (6.0) NSAIDS4 (3.4)COVID-19 symptoms, n (%) Upper respiratory97 (87) Gastrointestinal43 (39)COVID treatment, n (%) Steroids6 (5.4) Azithromycin20 (18) Hydroxychloroquine12 (11) Lopinavir/ritonavir0 (0) Tocilizumab1 (0.9) Remdesivir1 (0.9) Other antibiotics2 (1.9)COVID outcomes, n (%) ED visit18 (15) Hospitalization8 (6.8) Ventilation1 (0.9) ICU1 (0.9) Death0 (0)ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blockers; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; ED, emergency department; IBD, inflammatory bowel disease; ICU, intensive care unit; NSAIDS, nonsteroidal anti-inflammatory drugs; SD, standard deviation; TNF, tumor necrosis factor. Open table in a new tab ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blockers; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; ED, emergency department; IBD, inflammatory bowel disease; ICU, intensive care unit; NSAIDS, nonsteroidal anti-inflammatory drugs; SD, standard deviation; TNF, tumor necrosis factor.