key: cord-0993855-uczi9mzd authors: Blackett, John W.; Li, Jianhua; Jodorkovsky, Daniela; Freedberg, Daniel E. title: Prevalence and risk factors for gastrointestinal symptoms after recovery from COVID‐19 date: 2021-09-01 journal: Neurogastroenterol Motil DOI: 10.1111/nmo.14251 sha: 6c61896d7614b1b31b8c40b067da3f67301b8e95 doc_id: 993855 cord_uid: uczi9mzd BACKGROUND: COVID‐19 frequently presents with acute gastrointestinal (GI) symptoms, but it is unclear how common these symptoms are after recovery. The purpose of this study was to estimate the prevalence and characteristics of GI symptoms after COVID‐19. METHODS: The medical records of patients hospitalized with COVID‐19 between March 1 and June 30, 2020, were reviewed for the presence of GI symptoms at primary care follow‐up 1 to 6 months later. The prevalence of new GI symptoms was estimated, and risk factors were assessed. Additionally, an anonymous survey was used to determine the prevalence of new GI symptoms among online support groups for COVID‐19 survivors. KEY RESULTS: Among 147 patients without pre‐existing GI conditions, the most common GI symptoms at the time of hospitalization for COVID‐19 were diarrhea (23%), nausea/vomiting (21%), and abdominal pain (6.1%), and at a median follow‐up time of 106 days, the most common GI symptoms were abdominal pain (7.5%), constipation (6.8%), diarrhea (4.1%), and vomiting (4.1%), with 16% reporting at least one GI symptom at follow‐up (95% confidence interval 11 to 23%). Among 285 respondents to an online survey for self‐identified COVID‐19 survivors without pre‐existing GI symptoms, 113 (40%) reported new GI symptoms after COVID‐19 (95% CI 33.9 to 45.6%). CONCLUSION AND INFERENCES: At a median of 106 days after discharge following hospitalization for COVID‐19, 16% of unselected patients reported new GI symptoms at follow‐up. 40% of patients from COVID survivor groups reported new GI symptoms. The ongoing GI effects of COVID‐19 after recovery require further study. post-infectious IBS occurs in approximately 10% of patients after acute infectious gastroenteritis. 12, 13 Given the millions of people affected by COVID- 19 , even a small percentage with persistent GI symptoms would have important public health implications for patients and their providers. In this study, we sought to identify the prevalence, severity, and risk factors for GI symptoms in the months following initial infection with COVID-19, through both a retrospective analysis of patients hospitalized for COVID-19 with primary care follow-up at our institution, and through an online survey of "long-haulers" drawn from two COVID-19 support groups. This was a two-part study in which we determined the prevalence of new gastrointestinal symptoms during the months following diagnosis of COVID-19 using two fundamentally different cohorts. First, we performed a retrospective study of patients hospitalized with COVID-19 at our institution, using manual chart review to determine the prevalence of GI symptoms 1-6 months after hospital discharge. Second, we administered an online survey to users of two support groups for survivors of COVID-19 assessing the prevalence, type, and severity of GI symptoms, as well as risk factors and demographic information. In the first study cohort, we included all adult patients who were hospitalized for COVID-19 at Columbia University Irving based on the discharge diagnosis (such as women admitted for labor and delivery found to screen positive for SARS-CoV-2) were also excluded. Thus, the cohort included all adults admitted for COVID-19, whether or not they had any gastrointestinal symptoms at the time of admission. The primary outcome was the documentation of prespecified GI symptoms (diarrhea, abdominal pain, nausea or vomiting, and constipation) based on manual chart review at follow-up. Other covariates including age, sex, hospital length of stay, symptoms at presentation, intensive care unit or ventilator requirement, and history of anxiety or depression were also extracted from the electronic medical record. In the second study cohort, we administered an anonymous, online survey using Qualtrics to adult (≥18 years of age) users of two support groups for survivors of COVID-19 (www.reddit.com/r/covid 19pos itive, and Survivor Corps). The survey consisted of questions related to demographics, COVID-19 severity, and pre-COVID and post-COVID GI symptoms (complete survey available in the online Methods Supplement). Questions were designed to determine whether respondents met the Rome IV criteria for irritable bowel syndrome (IBS) with IBS questions pertaining to both pre--COVID-19 and post-COVID-19 symptoms so that we could clearly identify whether symptoms were new. 14, 15 Additional questions related to the current presence of gastrointestinal symptoms including abdominal pain, diarrhea, constipation, and nausea/vomiting were used to provide additional information about specific symptoms outside of the Rome criteria for IBS. Respondents also completed the IBS Symptom Severity Score (IBS-SSS), a validated survey used to determine the severity of IBS symptoms on a 0-500 point scale, with ≤175 indicating mild, 175-300 moderate, and ≥300 severe IBS. 16 The survey was administered between November 12 and December 15, 2020. The primary outcome was again the presence of post-COVID GI symptoms, defined as the report of any GI symptoms (same symptoms as above) post-COVID-19 that were not reported pre-COVID-19. For both parts of the study, continuous variables were compared in patients with and without persistent GI symptoms using the Student's t test or Mann-Whitney U test for non-parametric data. Categorical variables were compared using chi-square tests. A multivariable logistic regression model was also used to identify independent risk factors for ongoing GI symptoms, adjusting for predictors that were significant at alpha level 0.20. Among the unselected patients coming for routine follow-up visits, we sought to test whether the prevalence of GI symptoms diminished with increasing time from hospital discharge. To do this, the cohort was divided a priori into those presenting for follow-up from 30 to 89 days after hospitalization for COVID-19, 90-119 days after hospitalization, 120-149 days after hospitalization, and 150-180 days after hospitalization. The trend across the proportions of those with GI symptoms within each time interval was then assessed using the Cochran-Armitage test. Among the second study cohort of online survey respondents, the prevalence of GI symptoms meeting criteria for irritable bowel syndrome was compared before and after COVID- 19 After a median follow-up time of 106 days (IQR 78-141), 24/147 (16%) of patients had at least one ongoing GI symptom (95% confidence interval 11%-23%) at the time of their most recent followup appointment after hospitalization for COVID-19, which had not been present prior to their diagnosis of COVID-19. These included 10 patients with constipation (6.8%), 6 with diarrhea (4.1%), 6 with nausea/vomiting (4.1%), and 11 with abdominal pain (7.5%), with 14 patients having more than one symptom. An additional 5% of patients experienced transient GI symptoms at follow-up, which had resolved by the time of their latest clinic appointment. Among the 113 patients with at least 3 months of follow-up, the prevalence of ongoing abdominal pain in association with bowel disturbance (diarrhea or constipation) was 6.2%. As a point of comparison, the prevalence of post-infectious IBS after infectious gastroenteritis has been estimated at 10%, 12, 13 though it should be noted that this estimate varies widely depending on pathogen and definition used. Furthermore, the diagnosis of IBS requires at least 6 months of symptoms, which patients in this cohort did not have. Among patients hospitalized for COVID-19, the prevalence of constipation increased from 0% at hospital admission to 6.8% at most recent outpatient follow-up (p < 0.01). The prevalence of diarrhea decreased from 23% at admission to 4.1% at follow-up (p < 0.01). The prevalence of abdominal pain was similar at 6.1% at admission and 7.5% at follow-up (p = 0.64). The prevalence of nausea/ vomiting decreased from 21% at admission to 4.1% at follow-up (p < 0.01). The prevalence of each GI symptom present at the time of the most recent follow-up is shown in Table 1 . Women were significantly more likely to report new abdominal pain compared to men (14% vs. 1.3%, p < 0.01), though there was no significant difference in the prevalence of overall GI symptoms by sex (21% in women vs. 12% in men, p = 0.15). There were no significant differences in GI symptoms by age, race, or ethnicity. Prior history of depression was also a risk factor for persistent GI symptoms (28% vs. 13%, p = 0.04). The prevalence of persistent GI symptoms stratified by hospitalization characteristics is shown in Table 2 . While patients who had GI symptoms at initial presentation had a higher prevalence of persistent GI symptoms at follow-up, this difference was not statistically significant (22% vs. 14%, p = 0.21). Length of stay, intensive care unit admission, and use of antibiotics, steroids, or hydroxychloroquine were not associated with a higher prevalence of GI symptoms at follow-up. The peak laboratory values of inflammatory markers during hospitalization were also identified for each patient, and there were no significant differences in the median erythrocyte sedimentation rate, C-reactive protein, white blood cell count, ferritin, or interleukin-6 levels in patients with and without persistent GI symptoms at follow-up (Table S1 ). A multivariable logistic regression model was also used to evaluate for independent risk factors of ongoing GI symptoms at the time of follow-up (Table 3) . After adjusting for age, sex, and admission to intensive care unit (predictors that were significant at alpha level 0.20), only a history of depression remained significantly associated with the presence of GI symptoms at follow-up, with adjusted odds ratio 3.07, 95% confidence interval 1.04-9.04, p = 0.042). The prevalence of GI symptoms was 24% among patients whose most recent follow-up was 30-89 days after discharge, 20% for those 90-119 days post-discharge, 17% for those 120-149 days post-discharge, and 11% for those 150-180 days post-discharge There were 355 respondents to the online survey (229 from Survivor Corps and 126 from the COVID19positive Reddit group) who were ≥18 years of age and answered "yes" to the question "Have you been diagnosed with COVID-19." There were 70 respondents (20%) who reported a history of IBS or symptoms consistent with IBS prior to their COVID-19 diagnosis leaving 285 in the primary analysis. Among these, 91 (32%) reported diagnosis less than 1 month prior to the survey, 38 (13%) 1-3 months prior, 44 (15%) 3-6 months prior, and 112 (39%) more than 6 months prior. After excluding survey respondents with pre-existing IBS, there The characteristics of the survey respondents, excluding those with pre-existing IBS, is shown in Table 4 , comparing those with and without weekly abdominal pain with bowel disturbance after recovery from COVID-19. Women had a higher prevalence of GI symptoms, but the difference was not statistically significant (42% vs. 35%, p = 0.25). There was no association between post-COVID GI symptoms and TA B L E 1 Prevalence of gastrointestinal symptoms among 147 patients hospitalized for COVID-19 after a median 106 days of follow-up There was no significant association with the method of COVID-19 diagnosis. Those who had GI symptoms at the time of diagnosis were significantly more likely to report GI symptoms at follow-up (45% vs. 27%, p = 0.01), as were those who received antibiotics (51% vs. 35%, p = 0.02) or hydroxychloroquine (69% vs. 38%, p = 0.03). There were 134 survey respondents who were diagnosed with is likely to over-estimate the true prevalence of GI symptoms. We believe the true prevalence of persistent GI symptoms (meaning any symptoms for one month or more) after COVID-19 is likely between 16 and 40%, but much closer to the former than the latter. The prevalence of post-infectious IBS after acute gastroenteritis has been estimated at 10%. 12, 13 There are important caveats to recognize that prevent the direct comparison of this study's 16% prevalence of GI symptoms at a median of 3 months after COVID-19 to the 10% estimate of post-infectious IBS after acute gastroenteritis. First, patients in this study did not all have the length of follow-up time to meet the Rome IV criteria for IBS. When the definition for "persistent GI symptoms" within the unselected cohort was restricted to patients with both persistent abdominal pain and altered bowel habits for ≥3 months, the prevalence of abdominal pain with bowel disturbance fell to 6.2%. Second, the prevalence of GI symptoms ap- These data are intriguing, but it is unknown how well these selfidentified COVID-19 survivors represent the general population. "Long hauler" patients with persistent symptoms are more likely to complete surveys evaluating such symptoms and have the potential to create a powerful selection bias. Nonetheless, given the high numbers of patients with so-called "long COVID," it remains valuable to determine the prevalence and severity of gastrointestinal symptoms in this population. Our results suggest that in addition to dyspnea, fatigue, and "brain fog" symptoms, abdominal pain and altered bowel habits are common and can be severe. 4 5 However, they did not survey patients for abdominal pain or constipation. These studies were relatively limited in their assessment of persistent GI symptoms, so it is challenging to compare their results to ours. Some limitations should be mentioned. The retrospective cohort included only patients who were hospitalized during the early phase of the pandemic, when testing for SARS-CoV-2 was limited and often reserved for those with more severe symptoms. Therefore, it may not be generalizable to the broader population of all COVID-19 patients who typically have a milder course. As mentioned, due to the retrospective nature of the study, it was not possible to assess for the Rome IV criteria for post-infectious IBS. On the contrary, the online survey allowed for more precise questioning on symptom type, chronicity, and severity, in keeping with Rome IV. But this part of the study was limited by selection bias, as patients suffering from ongoing symptoms are more likely to be users of online support groups. In summary, new GI symptoms were common after COVID-19. This was true in unselected patients coming for routine primary care visits and more so among self-identified COVID-19 survivors in an online survey. Outpatient providers caring for COVID-19 survivors should be aware that GI symptoms may persist or develop after COVID-19 and the long-term GI impact of COVID-19 merits additional study. All authors declare that they have no conflicts of interest. JWB, DJ, and DEF contributed to study concept and design. The Columbia University Institutional Review Board approved this study. Anonymized data are available from the corresponding author upon reasonable request. John W. 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