key: cord-0690375-jwjo8dda
authors: D’Amico, Ferdinando; Danese, Silvio; Peyrin-Biroulet, Laurent
title: Systematic Review on Inflammatory Bowel Disease Patients With Coronavirus Disease 2019: It Is Time to Take Stock
date: 2020-08-07
journal: Clin Gastroenterol Hepatol
DOI: 10.1016/j.cgh.2020.08.003
sha: de7897653759ca00fd891d44155fb21390c17c78
doc_id: 690375
cord_uid: jwjo8dda

BACKGROUND & AIMS: Data on the clinical characteristics of patients with inflammatory bowel diseases (IBDs) with coronavirus disease 2019 (COVID-19) are scarce. The aim of our systematic review was to investigate symptoms and diagnostic–therapeutic management of IBD patients with COVID-19. METHODS: We searched PubMed, Embase, Web of Science, and MedRxiv up to July 29, 2020, to identify all studies reporting clinical information on adult and pediatric IBD patients with confirmed COVID-19. RESULTS: Twenty-three studies met our inclusion criteria, including 243,760 IBD patients. COVID-19 was diagnosed in 1028 patients (509 with Crohn’s disease [49.5%], 428 with ulcerative colitis [41.6%], 49 with indeterminate colitis [4.8%], and 42 with missing data [4.1%]), accounting for a cumulative prevalence of 0.4%. Viral infection occurred more frequently in males than in females (56.5% vs 39.7%), and the mean age ranged from 14 to 85 years. The most common symptoms were fever (48.3%), cough (46.5%), and diarrhea (20.5%), and a COVID-19 diagnosis was achieved mainly through polymerase chain reaction analysis of nasopharyngeal swabs (94.4%) and chest computed tomography scans (38.9%). Hydroxychloroquine (23.9%), lopinavir/ritonavir (8.2%), steroids (3.2%), and antibiotics (3.1%) were the most used drugs. Overall, approximately a third of patients were hospitalized (30.6%), and 11.4% of them required admission to the intensive care unit. In total, 29 COVID-19–related deaths were reported (3.8%), and increasing age and the presence of comorbidities were recognized as risk factors for COVID-19 and negative outcomes. CONCLUSIONS: Diarrhea occurs more frequently in IBD patients with COVID-19 than in the non-IBD population. Further studies are needed to define the optimal diagnostic–therapeutic approach in IBD patients with COVID-19.

T he severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new b-coronavirus that was identified in China after the onset, in December 2019, of some pneumonia cases of unknown etiology. 1 Viral infection can be asymptomatic or cause the coronavirus disease 2019 (COVID- 19) , which is characterized by a wide range of clinical manifestations including respiratory and gastrointestinal symptoms up to severe events such as pneumonia, acute respiratory distress syndrome, and death. 2 The high transmission capacity and the rapid virus spread worldwide have led the World Health Organization to declare a pandemic state and national and international authorities to impose several precautions and prohibitions to limit the contagion up to the total lockdown. 3, 4 As of June 12, 2020, there were 7,410,510 cases of COVID-19 that have been ascertained globally, with a total of 418,294 deaths. 5 Since the beginning of the health emergency, particular attention has been paid to the management of patients with chronic inflammatory bowel diseases (IBDs) because they frequently are treated with immunosuppressive drugs and therefore potentially are exposed to a greater infectious risk than the general population. 6 In addition, hospitals also profoundly have been reorganized to address the growing number of infected patients, to adapt to social distancing measures, and to prevent the infection risk, postponing or canceling nonessential activities and replacing outpatient visits with virtual clinics. 7, 8 The British Society of Gastroenterology, the European Crohn's and Colitis Organization, and the International Organization for the Study of Inflammatory Bowel Disease promptly provided empiric recommendations for the management of patients with Crohn's disease (CD) and ulcerative colitis (UC). [9] [10] [11] However, knowledge of SARS-CoV-2 evolves daily and some doubts persist on the optimal approach in subjects treated with immunosuppressants, biologics, or small molecules. The aim of our study was to provide a systematic overview of the literature data on IBD patients with COVID-19 to report the clinical characteristics of disease, to identify any risk factors for severe/complicated disease, and to investigate the diagnostic-therapeutic management of IBD patients in this emergency setting.

We conducted a systematic review in accordance with the Cochrane Handbook 12 and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension statement for reporting of systematic reviews incorporating network meta-analysis. 13 

We searched PubMed, Embase, Web of Science, and MedRxiv up to July 29, 2020, to identify all studies reporting information on IBD patients with COVID-19. The following medical subject heading terms were combined with the Boolean operators "AND" or "OR": "COVID-19," "coronavirus disease 2019," "SARS-CoV-2," "severe acute respiratory syndrome coronavirus 2," "new coronavirus," "Crohn's disease," "CD," "ulcerative colitis," "UC," "inflammatory bowel disease," "IBD." The search was restricted to human studies, although no language or time restrictions were applied. Titles and abstracts were scrutinized independently by all 3 authors (F.D., S.D., and L.P.B.) to identify eligible studies. Subsequently, full-text articles were examined for inclusion, and any disagreements were resolved through collegial discussion. Finally, the reference lists of the selected manuscripts were hand-searched to identify studies missed by the electronic search.

All studies meeting the following criteria were included: (1) adult and/or pediatric patients with a confirmed diagnosis of IBD; (2) studies reporting at least 1 confirmed case of COVID-19; and (3) studies addressing clinical management of IBD patients with COVID-19.

Reviews, systematic reviews, meta-analyzes, guidelines, letters, and editorials that did not show original data were excluded from our work. Furthermore, all studies involving non-IBD patients were excluded if the IBD population data could not be distinguished. If some results were reported at multiple time points, the study with the most comprehensive data was included.

Each article was assessed qualitatively. All 3 authors extracted the following data from the selected studies: first author, journal and year of publication, study design, number of participants, patient characteristics (age, sex, concomitant treatments, IBD type), number of IBD patients with confirmed COVID-19, symptoms of COVID-19, diagnostic approach, COVID-19 therapy, hospitalizations, admission to the intensive care unit (ICU), number of deaths, and risk factors associated with COVID-19.

The Newcastle-Ottawa Scale (NOS) score was used to measure the quality of nonrandomized clinical trials, and the Jadad score was adopted for randomized clinical trials. 14, 15 The NOS score ranges from 0 to 9. The NOS score is based on 8 items: representativeness of the exposed cohorts, selection of the nonexposed cohort, ascertainment of exposure, demonstration that the outcome of interest was not present at the start of the study, comparability of cohorts on the basis of the design or analysis, assessment of the outcome, follow-up period is long enough for outcomes to occur, and adequacy of the follow-up evaluation. One point can be assigned to each item, except for cohort comparability (which can be What You Need to Know Background Little data are available on the clinical characteristics of inflammatory bowel disease (IBD) patients with COVID-19 and their diagnostic-therapeutic management is not well established.

IBD patients with COVID-19 have symptoms similar to IBD patients except for a higher percentage of diarrhea. The diagnostic-therapeutic approach does not differ between IBD and non-IBD patients with COVID-19.

Fecal test for new coronavirus detection could allow to differentiate infected patients from those with IBD re-exacerbation. In addition, IBD medications could play a role in the treatment of COVID-19. assigned 2 points). A NOS score of 6 or higher was associated with high-quality studies, while scores of 3 or lower or between 4 and 5 indicated low-and moderatequality studies, respectively. On the other hand, the Jadad score ranges from 0 to 5 and it assesses the following parameters: randomized study, appropriate randomization, double-blind study, appropriate double-blind study, and a description of withdrawals/dropouts. Each parameter is assigned 1 point and a study is defined as a high-quality study if the Jadad score is 3 or higher. All 3 authors graded the studies independently and any disagreements were discussed until their resolution.

The flow chart of the search process is detailed in Figure 1 . A total of 1380 articles were identified through our search (PubMed, 183; Embase, 84; Web of Science, 22, and MedRxiv, 1091). After removing duplicates and reviewing titles and abstracts, 63 studies were evaluated for full-text analysis. An additional 40 studies were excluded because they did not include COVID-19 patients (n ¼ 25), did not evaluate clinical data (n ¼ 9), results were included in another study (n ¼ 3), data of IBD patients with a confirmed diagnosis of COVID-19 could not be extrapolated (n ¼ 2), or data were not original (n ¼ 1). Finally, 23 studies were included in our systematic review. Most studies were case reports (12 [52.2%]), 16, 18, 19, 22, 27, 29, [32] [33] [34] [35] [36] 38 17, 18, 21, [23] [24] [25] 29 (Table 3) .

The overall study population consisted of 243,760 IBD patients. 16, 17, 20, [23] [24] [25] [26] 31, 37, 38 pediatric cases (<18 y) were reported in 4 studies (17.4%), 21, 29, 30, 36 and an infected pregnant patient was described in 1 case report (4.3%). 27 The ongoing drugs at the time of COVID-19 diagnosis were reported in almost all studies (20 [87.0%]) 16 

Eighteen studies (78.3%) [16] [17] [18] [19] [20] 22, 23, [25] [26] [27] [28] [31] [32] [33] [34] [35] [36] 38 evaluated the diagnostic approach in IBD patients with COVID-19. The polymerase chain reaction (PCR) analysis of the nasopharyngeal swabs was the most commonly adopted method (17 of 18 [94.4%]). [16] [17] [18] [19] [20] 22, 23, 25, 27, 28, [31] [32] [33] [34] [35] [36] 38 A chest computed tomography was performed in 7 studies (38.9%). 16, 19, 22, 25, [32] [33] [34] [35] In 1 study (5.6%), 26 the diagnosis was achieved by laboratory test. The treatment of infected subjects was described in 14 articles (60.1%). 16, 18, [20] [21] [22] [23] 27, 29, [32] [33] [34] [35] [36] 38 (Table 5) . Importantly, in 3 case reports the patients were treated with infliximab 29,33 or tofacitinib. 18 

The percentage of severe COVID-19 (need for hospitalization, admission to the ICU, or mechanical ventilation) was reported in 21 articles (91.3%). [16] [17] [18] [19] [20] [21] [22] [23] 25, [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] Overall, 302 of 987 patients (30.6%) were hospitalized and only a small part of them stayed in the ICU (28 of 246 [11.4%] ). In 17 studies [16] [17] [18] [19] [21] [22] [23] 25, 27, 29, 30, [32] [33] [34] [35] [36] 38 the need for mechanical ventilation was described, with an average value of 3.7% patients (26 of 697). Moreover, the percentage of IBD patients who died from COVID-19 was investigated in all studies except 2, 26,37 with a total of 29 deaths in 760 cases (3.8%). It is noteworthy that in only 2 studies 17,37 was there a control group consisting of non-IBD patients with COVID-19. Interestingly, death and ICU admission were numerically lower in the IBD group than in the control group (24% vs 35%, respectively; P ¼ .352). 17 NOTE. Items were as follows: 1, representativeness of the exposed cohort; 2, selection of the nonexposed cohort; 3, ascertainment of exposure; 4, demonstration that the outcome of interest was not present at the start of the study; 5, assessment of the outcome; 6, follow-up period was long enough for outcomes to occur; 7, adequacy of follow-up evaluation (>75% follow-up evaluation, or description for those lost); 8, comparability of cohorts on the basis of the design or analysis. Single stars, 1 point; double stars, 2 points.

95% CI, 1.80-153.9; P ¼ .01) were associated with COVID-19-related deaths. 25 

This was a systematic review reporting the prevalence, clinical characteristics, diagnostic/therapeutic management, and risk factors of IBD patients with a confirmed diagnosis of COVID-19. Twenty-three studies were included showing a COVID-19 prevalence of 0.4% in our IBD cohort. COVID-19 was found in more men than women (56.5% vs 39.7%), and patients of all ages, from children to the elderly, were involved also, as highlighted in the first reports from China on non-IBD individuals. 2, 39 In line with general population data, 2 fever (48.3%) and cough (46.5%) were the most frequent symptoms in infected patients with IBD. Interestingly, approximately a fifth of the patients experienced diarrhea. Our previous pooled analysis 40 and 2 recent systematic reviews and meta-analyses 41, 42 showed a cumulative prevalence of diarrhea of approximately 7% to 10% in patients with COVID-19. This high disparity could be related to the influence of the underlying disease on the number of evacuations, justifying the greater percentage of diarrhea in CD and UC patients than in the general population. On the other hand, SARS-CoV-2 has been isolated in the duodenum and rectum, 43 and a higher concentration of fecal calprotectin, a known inflammatory marker, has been found in infected patients with diarrhea compared with those without diarrhea (123.2 vs 17.3 mg/g; P < .001), 44 suggesting that viral gut tropism could worsen inflammatory status and symptoms of IBD patients. Unfortunately, it is extremely challenging to assign the symptom to the underlying disease or to the concomitant infection, making it difficult to interpret data. A COVID-19 diagnosis was achieved mainly through nasopharyngeal swabs (94.4%) and chest computed tomography scans (38.9%) .

Surprisingly, although approximately 40% of stool samples have been reported as positive for fecal SARS-CoV-2, 42 no test for the presence of viral RNA shedding in the stool was performed in the included studies. To date, no clear evidence is available on the sensitivity of fecal PCR for the diagnosis of COVID-19. However, we hypothesize that fecal PCR may be useful in IBD patients to distinguish disease re-exacerbation from viral superinfection, allowing better patient management and targeted therapy. Hydroxychloroquine (23.9%) and lopinavir/ritonavir (8.2%) were the most frequently administered drugs in our cohort. Hydroxychloroquine is an antimalarial drug that proved to be effective in inhibiting in vitro replication of the new coronavirus. 45 However, data supporting its use in infected patients are still limited. A prospective observational study 46 conducted on 1376 patients with COVID-19 showed no 18, 29, 33 clinical remission of IBD patients with COVID-19 was achieved after treatment with infliximab or tofacitinib. These findings certainly are not sufficient to support the use of these drugs, but they provide numerous insights. Accumulating evidence has shown that COVID-19 severity is associated with a cytokine storm syndrome, characterized by an increase in interleukin 2, interleukin 7, granulocytecolony stimulating factor, interferon-g-inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-a, and tumor necrosis factor-a. 48 Based on these findings, it is legitimate to hypothesize that the use of biological drugs that selectively inhibit specific cytokines or small molecules that simultaneously block multiple cellular pathways may play a role in the treatment of these patients. In addition, the mortality rate that we found in IBD patients with COVID-19 (3.8%) was lower compared with the general population (w10%). 49, 50 This could be explained by a lower rate of COVID-19 risk factors (increasing age and comorbidities) in IBD subjects. Importantly, more than half of the patients included in our study were treated with biologics or small molecules at the time of COVID-19 diagnosis, but it is not known if these drugs influenced the prognosis of infected IBD patients. Several ongoing studies are recruiting patients to assess the efficacy and safety of biologics (NCT04344249 and NCT04425538) and small molecules (NCT04373044, NCT04346147, and NCT04362943) for COVID-19 treatment and will allow us to understand if these drugs can be used in this setting.

Our systematic review addressed several practical aspects of managing IBD patients with COVID-19, including moderate-to high-quality studies and reporting data from a relevant number of patients. However, some limitations must be mentioned. First, no randomized clinical trial has been conducted to date in patients with IBD. Second, we excluded all studies reporting data collected in the Surveillance Epidemiology of Coronavirus Under Research Exclusion-Inflammatory Bowel Disease registry, but any overlaps resulting from nonexplicit inclusion in the registry cannot be excluded. Nonetheless, the description of clinical symptoms was missing in the Surveillance Epidemiology of Coronavirus Under Research Exclusion-Inflammatory Bowel Disease database, although most of the evaluated articles provided this important information.

In conclusion, symptoms experienced by IBD patients with COVID-19 are similar to those occurring in the general population, except for a higher percentage of diarrhea. Currently, the diagnostic-therapeutic approach does not differ between IBD and non-IBD patients, but further studies are needed to evaluate whether fecal research of viral RNA and treatment with IBD drugs may play a role in the management of COVID-19 patients.

COVID-19, coronavirus disease

IBD, inflammatory bowel disease. References

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e-mail: peyrinbiroulet@gmail. com; fax: (33) 383153633. Conflicts of interest These authors disclose the following: Silvio Danese has served as a speaker, consultant and advisory board member for Schering-Plough