key: cord-306760-05my504t
authors: Turner, Dan; Huang, Ying; Martín-de-Carpi, Javier; Aloi, Marina; Focht, Gili; Kang, Ben; Zhou, Ying; Sanchez, Cesar; Kappelman, Michael D.; Uhlig, Holm H.; Pujol-Muncunill, Gemma; Ledder, Oren; Lionetti, Paolo; Dias, Jorge Amil; Ruemmele, Frank M.; Russell, Richard K.
title: Corona Virus Disease 2019 and Paediatric Inflammatory Bowel Diseases: Global Experience and Provisional Guidance (March 2020) from the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology, and Nutrition
date: 2020-03-31
journal: J Pediatr Gastroenterol Nutr
DOI: 10.1097/mpg.0000000000002729
sha: 
doc_id: 306760
cord_uid: 05my504t

INTRODUCTION: With the current coronavirus disease 2019 (COVID-19) pandemic, concerns have been raised about the risk to children with inflammatory bowel diseases (IBD). We aimed to collate global experience and provide provisional guidance for managing paediatric IBD (PIBD) in the era of COVID-19. METHODS: An electronic reporting system of children with IBD infected with SARS-CoV-2 has been circulated among 102 PIBD centres affiliated with the Porto and Interest-group of ESPGHAN. A survey has been completed by major PIBD centres in China and South-Korea to explore management during the pandemic. A third survey collected current practice of PIBD treatment. Finally, guidance points for practice have been formulated and voted upon by 37 PIBD authors and Porto group members. RESULTS: Eight PIBD children had COVID-19 globally, all with mild infection without needing hospitalization despite treatment with immunomodulators and/or biologics. No cases have been reported in China and South Korea but biologic treatment has been delayed in 79 children, of whom 17 (22%) had exacerbation of their IBD. Among the Porto group members, face-to-face appointments were often replaced by remote consultations but almost all did not change current IBD treatment. Ten guidance points for clinicians caring for PIBD patients in epidemic areas have been endorsed with consensus rate of 92% to 100%. CONCLUSIONS: Preliminary data for PIBD patients during COVID-19 outbreak are reassuring. Standard IBD treatments including biologics should continue at present through the pandemic, especially in children who generally have more severe IBD course on one hand, and milder SARS-CoV-2 infection on the other. SUPPLEMENTAL DIGITAL CONTENT: An infographic accompanying this article can be found at.

(JPGN 2020;70: 727-733)

A global pandemic of coronavirus disease 2019 is now apparent. SARS-CoV-2 infection resulting in coronavirus disease 2019 causes significant pulmonary disease in adults leading to intensive care and sometimes death. The impact in adults including on mortality is greater in patients with chronic diseases.

The first paediatric inflammatory bowel disease cases to have SARS-CoV-2 infection have been described. Coronavirus disease 2019 in children, including paediatric inflammatory bowel disease, appears to be mild. Standard paediatric inflammatory bowel disease treatments should continue since delay in infusions in endemic areas has been associated with disease flare. C oronavirus disease 2019 is caused by the zoonotic coronavirus SARS-CoV-2 and started in China in December 2019 (1) . By March 2020, it had been declared by WHO as a global pandemic. It is predominantly spread by airborne droplets but there is also viral shedding in stool, giving the potential for faecal-oral transmission (2, 3) . In adults, COVID-19 predominantly presents with cough and fever resulting in a proportion of patients developing acute respiratory distress syndrome (ARDS) (4) . SARS-CoV-2 infection may also cause gastrointestinal symptoms (5, 6) . The disease course of COVID-19 in children is predominantly benign with mild or even no symptoms, and almost no reported mortality (6) (7) (8) . The severe pulmonary involvement of the virus may be caused also by hyperinflammation and a secondary hemophagocytic-lymphohistiocytosis (HLH)-like presentation (9, 10) .

SARS-CoV-2 enters cells via the angiotensin-converting enzyme-2 (ACE-2) receptor that is abundantly expressed in cells of the lungs, oral cavity, and the gastrointestinal tract. Lymphopenia and elevated C-reactive protein (CRP), ferritin and lactate dehydrogenase levels are associated with a more severe course (11) . Increased levels of cytokines and chemokines, such as interleukin-6 (IL- 6) , have been associated with increased disease severity in adults (11) and children (5) . It seems that the most severe presentations of COVID-19 result from hyperinflammatory cytokine responses in particularly dysregulated IL-6-dependent acute phase responses associated with a decrease in cytotoxic T and natural killer (NK) cells. Those findings explain why in addition to antiviral therapies, immunomodulatory therapies and passive immunisation strategies could potentially be considered to improve outcome in severely affected patients (10) . Consistent with this hypothesis is the report that in an endemic area, only 3 children receiving immunosuppressant medication for liver transplantation developed SARS-CoV-2 infection and none were severe (12) .

The coronaviruses, SARS-CoV and MERS-CoV, were responsible for previous epidemics. Although clinical and immunological data from these viruses cannot directly be translated to predict interventions in SARS-CoV-2 infections, it is noteworthy that thiopurine metabolites, 6-mercaptopurine and 6-thioguanine, have been shown to have direct antiviral activity by inhibiting the papain-like protease of both viruses (13) as well as host proteins involved in antiviral response (14) . Systemic steroids, however, did not confer substantial clinical benefit (15) . Indeed, the safety of corticosteroids during COVID-19 is unclear (16) , but it seems that if used for short periods and at a low dose they are not related to a worse prognosis, even in patients with COVID-19 pneumonia (17) . There are no published data about the safety of monoclonal antibodies during this infection although anti-IL-6 receptor antibody has been used in a few patients with COVID-19 with promising results (18) . Current literature related to other viral infections does not indicate stopping these treatments or modifying therapeutic regimes (19) . In light of the hyperinflammatory immune response seen in patients with COVID-19 it is highly relevant that blockade of IL-6R with tocilizumab resulted in clinical improvement associated with normalisation of fever, lymphocyte counts, and CRP in a retrospective group of 21 adults with severe SARS-CoV-2 infection (20) . Locally active medications, such as anti-a4b7 (eg, vedolizumab) or budesonide are unlikely to have a major impact on systemic nor pulmonary SARS-CoV-2 responses.

Despite the above, the IBD-related immunosuppressive treatment has raised concerns regarding the management of COVID-19 with potential implications for treatment, isolation, and routine hospital attendance (19, 21) . Provisional reports from adult IBD centres in China are reassuring (22) , and as some of the pulmonary damage may be caused by autoinflammatory response of the host, immunosuppressive medication have even been postulated to protect from severe disease (9, 10) . Nonetheless, children may have different recommendations than adults, given the overall milder course of the infection. In addition, IBD in children tends to be more extensive and severe than adults with consistently higher need for immunomodulators and biologics. We thus aimed to collate available data on paediatric IBD (PIBD) and SARS-CoV-2 globally and to develop consensus statements for the management of PIBD during the COVID-19 pandemic. The consensus process included specialists in paediatric IBD from the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN).

Following an open call to the members of the Paediatric IBD Porto group of ESPGHAN, international experts were selected as the writing group. In addition to Porto group members, external paediatric experts from China (Y.H. and Y.Z.) and South Korea (B.K.), being the first endemic areas, were invited to participate, as well as a representative from the SECURE-IBD registry (M.K.).

A REDCap reporting system has been constructed to collect all COVID-19 cases among children with IBD in the 102 Porto group-affiliated paediatric IBD centres in Europe (and several beyond). We asked for cases with a virological confirmation of SARS-CoV-2, but to avoid reporting bias of the more severe cases we allowed also highly suspected cases when testing was not available as per local testing policy since several countries permit testing only those with evidence of pneumonia (eg, France and Spain). Nonetheless, the suspected cases were labelled and justified individually based on both typical symptoms and close contact with a confirmed case. A 7-day follow-up was required to ensure capturing of the disease severity. The registry included demographic questions as well as pre-infection IBD clinical explicit details, treatments, and outcomes. The ethics committee of Shaare Zedek Medical Center, Jerusalem, waived the need for approval, given the urgent need for reporting clinical experience and as the report was retrospective, anonymous, and without contacting patients. For the SECURE IBD cases, the UNC-Chapel Hill Office for Human Research Ethics has determined that storage and analysis of deidentified data does not constitute human subjects research as defined under federal regulations (45 CFR 46.102 and 21 CFR 56.102) and does not require IRB approval.

A survey among members of the Porto Group on changes in common practice in this new situation was launched via online platform in March 22, 2020. Investigators working in 32 tertiary centers around Europe, Israel, and Canada completed the survey. Different topics related to how the centers have adapted to COVID-19 outbreak were collected, both regarding therapeutic strategies and in the logistic organization of the PIBD units.

A questionnaire was sent on March 20, 2020 to 19 paediatric gastroenterology centers in China to evaluate the impact of COVID-19 on the prognosis of IBD children. These centers were distributed across 15 cities including Shanghai, Beijing, Guangzhou, Shenzhen, Hangzhou, Chongqing, Chengdu, Wuhan, Changsha, Zhengzhou, Xi'an, Xiamen, Guiyang, Nanjing, and Shenyang, in total care for 1431 children with IBD.

A questionnaire was sent on March 19, 2020 to 4 tertiary centres in the metropolitan city of Daegu and in Gyeonsangbuk-do province where the majority of the total South-Korean COVID-19 infection cases have been confirmed. Data regarding the changes in medication prescription by physicians, changes in hospital visits, medication administration, and disease exacerbation were collected since January 20, 2020, the date of the first COVID-19 occurrence in South Korea.

On the basis of the above collective data and literature review, the writing group formulated guidance points, which were sent to all members of the Porto group of ESPGHAN for comments and electronic voting (Appendix). It has been decided a priori that consensus is reached by at least 80% of voters.

On the basis of the literature review, the initial global experience described below and the practice surveys, 12 statements were formulated and agreed upon by the writing group. Voting by the 37 Porto-group members and the authors retained 10 of which (Table 1) Postponing clinics except those experiencing flares or new diagnosis has been practiced by 40% of centres. Of the 32 centres, 31 (97%) encourage their patients not to make any changes in current treatments in response to COVID-19; drug doses and infusion intervals were not changed and combination therapy was continued. Children requiring infusions (ie, infliximab, vedolizumab) continued with the same regimen. Twenty-nine centers (91%), including endemic areas in Europe, had no limitations in the administration of parenteral drugs. Other actions implemented in the various centers included facilitating drug administration to the patients (eg, modifying pharmacy opening hours, and increasing the number of dispensed doses) and limiting or stopping nonurgent endoscopic procedures.

Seven children with IBD and COVID-19 have been reported until March 26, 2020 by the 102 sites affiliated with the Paediatric IBD Porto group of ESPGHAN ( Table 2) . All cases had a mild infection without the need for admission despite treatment with immunosuppressive medications, steroids, and/or biologics.

The underlying IBD remained generally stable during the infection and the IBD-related medications were not held in any of the cases.

Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) is an international registry to monitor and report on outcomes of COVID-19 occurring in IBD patients. As of April 4, 2020, 264 adults and 11 children with confirmed COVID-19 infection have been reported. Similar to the Porto group cases, the 11 paediatric patients had mild course of COVID-19 and did not require hospitalization (known clinical data of the first case is added to Table 2 ). A total of 79 adult patients have been hospitalised and 12 died, all older than the age 33 and 9 of whom older than 65 years of age.

We provide the first document on the global impact of SARS-CoV-2 infection on paediatric IBD to date, from which we have generated guidance points for paediatric gastroenterologists in the era of this COVID-19 pandemic. The general message of continuing current IBD treatments is supported by the Chinese and South Korean experience reported here of $20% disease exacerbation in children whose infliximab infusions were delayed. 

Consensus rate 1. IBD per-se does not currently seem to be a risk factor for acquiring SARS-CoV-2, nor for a more severe infection. 100% 2. For decreasing the risk of contracting SARS-CoV-2 in children with IBD, we recommend using the same measures as in the local population during the pandemic (eg, good hand hygiene, avoiding contact with anyone with respiratory symptoms and social distancing).

3. When possible by local situation and resources, children should continue follow-up visits to ensure appropriate monitoring of the disease. Remote telemedicine consultations, along with the use of surrogate markers of inflammation (fecal calprotectin, C-reactive protein, patient-reported outcomes) may, however, be an alternative to face-to-face office visits during the epidemic, especially for those in remission. The option of delaying visits should be considered on an individual basis.

4. Active IBD disease should be treated according to the standard guidance PIBD protocols as before the epidemics, as the risk of IBD complications in active IBD outweighs any risk of COVID-19 complications, especially in children.

5. There is currently no concrete evidence that any of the IBD treatments increases the risk for acquiring SARS-CoV-2 or for a more severe infection once infected. Therefore, uninfected children should generally continue their medical treatment, including immunomodulators and biologic therapies, as the risk of a disease flare outweighs any estimated risk of SARS-CoV2 infection. This is especially true in children who have a much milder infection. Specific considerations are listed below.

6. Corticosteroids can be used to treat disease relapses, but as always recommended in children, the drug should be weaned as soon as possible. In Crohn disease, exclusive enteral nutrition should be preferred. 8. Switching from infliximab to adalimumab in a stable child should be discouraged unless impossible to provide intravenous infusions, as the risk of disease exacerbation after such a switch has been documented in the clinical trial setting.

9. There is no clear indication to stop IBD treatment during COVID-19 infection, also because of the typical prolonged effect of IBD drugs. Nonetheless, we recommend suspending immunosuppressive treatment during an acute febrile illness until fever subsides and the child returns to normal health, irrespective of the SARS-CoV-2 testing status. In case of positive SARS-CoV-2 testing in an asymptomatic child, the decision of therapeutic changes should be individualized. Mesalamine should never be suspended.

10. Elective surgeries and nonurgent endoscopies should be postponed during the epidemic. 97%

All statements are limited to children and are based on the emerging but limited data available upon March 2020; it is possible that statements may change as data on PIBD and COVID-19 will accumulate. The following 2 statements did not receive consensus of the Porto group, and thus were removed: ''Up to onethird of patients with COVID-19 may present with gastrointestinal symptoms, mainly diarrhea or nausea. Therefore, these symptoms during an active infection do not necessarily indicate a flare of the underlying IBD'' and ''In children with suspected symptoms of COVID-19, SARS-CoV2 testing is recommended before any therapeutic change''. COVID-19 ¼ corona virus disease 2019; IBD ¼ inflammatory bowel disease; PIBD ¼ paediatric inflammatory bowel disease.

We provide the first case series of children with IBD who have SARS-CoV-2 infection, all cases were mild despite being treated with immunosuppressive medications. These reassuring cases are supported by the lack of symptomatic disease among children with PIBD cases in China and South Korea. As SARS-CoV-2 infection is often asymptomatic in children, it is likely that the true mild/minimal infection rate is higher than identified. Among 171 Chinese children with COVID-19, nearly a quarter had no symptoms (8) . The reason for the milder infection course in children, resulting in lower hospitalisation rate and mortality, is not yet clear. Our observation of mild or minimal SARS-CoV-2 infection in children with IBD despite treatment with immunosuppressive medications is further supported by observations in children with liver disease on immunosuppression in Northern Italy where only 3/700 were documented to have SARS-CoV-2 infection and none with a severe course (12) . The larger case series of adults reported from the SECURE-IBD registry show that current outcomes do not vary substantially from reports from the general population infected with SARS-CoV-2. SECURE-IBD cases may be biased towards more severe cases as only confirmed infections have been reported and in many countries, asymptomatic and mild infections are not tested for the virus by local policy. Careful continuous monitoring of the data is needed to base future possible adjustments to the current guidance.

On the basis of currently (March 2020) available limited data presented here, we suggest the following: IBD children, with and without immunosuppressive and biological therapy, do not seem to carry a higher risk of SARS-CoV-2 infection, compared with the general population. We can cautiously suggest that currently there is no signal indicating worsening the COVID-19 course by IBDrelated treatment. On the other hand, the risk of inappropriate management of IBD driven by the fear of the virus may have a significant impact on the health of IBD patients as indicated by increased flares with delayed therapy in China and South Korea. Therefore, there is presently no justification to support adaptation of therapies for children with IBD in the light of the currently ongoing SARS-CoV-2 pandemic, especially in children who have in general a more extensive and severe IBD on one hand and milder COVID-19 course on the other. Managing disease relapses in this period in epidemic areas can be difficult, thus it is crucial to advise patients to maintain their therapies, particularly when in remission. These interim conclusions may be adjusted in the future based on emerging data on COVID-19 in children with IBD.

ESPGHAN is not responsible for the practices of physicians and provides guidelines and position papers as indicators of best practice only. This guidance may be revised as necessary to account for changes in technology, new data, or other aspects of clinical practice. This guidance is intended to be an educational device to provide information that may assist clinicians in providing care to patients. They are not a rule and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring, or discouraging any particular treatment. Clinical decisions in any particular case involve a complex analysis of the patient's condition and available courses of action. Therefore, clinical considerations may require taking a course of action that varies from the suggestions made as part of this guidance. ¼ weighted paediatric CD activity index. The two suspected cases: household first-degree relative had concurrent confirmed infection but the child was not tested as per local testing policy as they has only mild presentation. None required admission. None of the IBD-related medications were stopped because of the SARS-CoV-2 infection. No worsening of the IBD has been reported in any of the children. Patient numbers 1 to 7 did not suffer from other chronic disease; patient number 8 had cardiovascular disease. Cases reported from the Porto group sites in: France, United Kingdom, Italy, Spain, Israel; Case number 8 was reported from the SECURE-IBD registry.

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Shengjing Hospital of China Medical University

Hunan Children's Hospital

Sitang Gong, Guangzhou Women and Children's Medical Center

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3 years received consultation fee or honorarium from Abbvie, Nestlé Health Science. P.L., Advisory board and conferences for Abbvie, Pfizer, Sandoz, Nestlè, Nutricia. M.D.K. for the last 3 years received consultation fees from Abbvie, Janssen, Takeda, and Lilly; shareholder of Johnson & Johnson, research support from Abbvie and Janssen. JAD received consultation fee from Adacyte and honorarium for lectures from Danone, Ferrer. F.M.R. for the last 3 years received consultation fee, research grant, or honorarium from Janssen, Pfizer, Abbvie, Takeda, Celgene, Nestlé Health Science, Nestlé Nutrition Institute. C.S., Y.H., and Y.Z. report no conflicts of interest. This article has been developed as a Journal CME Activity by NASPGHAN.Visit http://www.naspghan.org/content/59/en/Continuing-Medical-Educa tion-CME to view instructions, documentation, and the complete necessary steps to receive CME credit for reading this article. Copyright # 2020 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000002729