What Is Known
- 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.
What Is New
- 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.
Coronavirus disease 2019 (COVID-19) 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 (6–8). 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-α4β7 (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.).
Paediatric Porto Group Reporting System
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 de-identified 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.
Porto Group Survey
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.
South Korean Survey
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), all endorsed with a consensus of at least 92%.
The Chinese Experience of Paediatric Inflammatory Bowel Disease Management During Corona Virus Disease 2019 Outbreak
A total of 917 confirmed and suspected paediatric cases of COVID-19 were reported in the 19 Chinese paediatric gastroenterology centres who participated in the survey (84% from Wuhan), none had a diagnosis of IBD. Between January 20 and March 20, 233 PIBD children should had received scheduled infliximab infusions, of whom 66 (28%) had their infusions delayed because of the epidemic by 1 to 8 weeks (average delay 19.2 ± 11.5 days) and 2 (0.9%) discontinued infusions temporarily. Among the 66 patients with delayed infusions, 14 (21%) experienced a disease exacerbation, of whom 10 (15%) required an admission (average length of hospital stay 10.4 ± 6.0 days). In comparison, only 17 children (1.2%) of the 1431 PIBD Chinese children had disease exacerbation during that period because of other causes (including poor compliance to therapy [n = 10], uncontrolled primary disease [n = 5] and Clostridium infection [n = 2]).
The South Korean Experience of Paediatric Inflammatory Bowel Disease Management During Corona Virus Disease 2019 Outbreak
Among the 8,413 confirmed infections with SARS-CoV-2 in South Korea as of March 18, 2020 (23), 87 (1.03%) were between 0 and 9 years, and 438 (5.2%) were in the age group 10 to 19 years; none died. The proportion of patients 19 years or less with confirmed COVID-19 (6.2%) was much less than the proportion of the country's population as reported by the local statistics bureau (18%; 9,315,774 among 51,629,512).
In the city of Daegu and Gyeonsangbuk-do province, where 87% of the total South Korean COVID-19 infection cases have been confirmed, there are 4 tertiary pediatric centres following in total 272 children with IBD. These centres continued following children with IBD at the outpatient clinics with 297 face-to-face appointments and 52 remote consultations. During this 2-month period, biologics and immunomodulators have been prescribed without changes in doses or intervals in almost all children (99.3%). No cases of COVID-19 infection have been reported in South Korean children with IBD. Thirteen families (4.8%) have postponed their anti-TNF treatment because of parental anxiety about the virus, of whom 3 (23%) had worsening in their Crohn disease activity. The median delay in scheduled anti-TNF administration in these patients was 17 days (range 14–22 days).
Porto Group of European Society of Paediatric Gastroenterology, Hepatology, and Nutrition Practice During the Corona Virus Disease 2019 Outbreak
Of the current 35 members of the Porto group of ESPGHAN, 32 (91%) responded to the survey of their practice during the COVID-19 outbreak, representing 32 PIBD referral centers in Europe, Israel, and Canada. Some of the face-to-face visits have been changed to remote visits in 97% of PIBD centers. Thirty centers (94%) tried to limit patients attending the hospital if not strictly needed (exceptions are flares, drug collection, or infusions). 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.
Paediatric Inflammatory Bowel Disease Cases With Confirmed or Highly Suspected SARS-CoV-2 Infection
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.
Experience of Corona Virus Disease 2019 and Inflammatory Bowel Disease in Adults
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.
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 IBD-related 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.
Appendix: Other Contributing Co-authors
Porto and Interest Group of ESPGHAN Members Participating in the Survey and/or Voting on Statements
- Dan Turner, Jerusalem
- Richard K Russell, Edinburgh
- Eytan Wine, Edmonton
- Javier Martín-de-Carpi, Barcelona
- Jorge Amil Dias, Porto
- David Wilson, Edinburgh
- Arie Levine, Holon
- Marina Aloi, Rome
- Frank Ruemmele, Paris
- Anne Griffiths, Toronto
- Lissy de Ridder, Rotterdam
- Johanna Escher, Rotterdam
- Victor Manuel Navas-López, Málaga
- Paolo Lionetti, Florence
- Stephan Buderus, Bonn
- Johan Van Limbergen, Amsterdam
- Patrick van Rheenen, Groningen
- Christina Almuthe Hauer, Graz
- Nadeem Afzal, Southampton
- Nick Croft, London
- John Fell, London
- Gigi Veereman, Brussels
- Sibylle Koletzko, Munich
- Jean Pierre Hugot, Paris
- Margaret Sladek, Cracow
- Annamaria Staiano, Naples
- Kaja Leena Kolho, Helsinky
- Christian Braegger, Zurich
- Ola Olén, Stockholm
- Seamus Hussey, Dublin
- Dror Shouval, Tel Aviv
- Amit Assa, Petach Tiqva
- Jiri Bronsky, Prague
- Holm Uhlig, Oxford
- Iva Hojsak, Zagreb
- Lorenzo Norsa, Bergamo
- Cesar Sanchez, Madrid
- Gemma Pujol-Muncunill, Barcelona
- Oren Ledder, Jerusalem
Chinese Centres Participating in the Survey
- Ying Zhou, Ying Huang, Department of Gastroenterology, National Children's Medical Center, Children's Hospital of Fudan University
- Chundi Xu, Ruijin Hospital, Shanghai Jiaotong University School of Medicine
- Hongmei Guo, Yu Jin, Children's Hospital of Nanjing Medical University
- Hong Mei, Wuhan Children's Hospital
- Jie Chen, The Children's Hospital, Zhejiang University School of Medicine
- Jingfang Chen, Xiamen Children's Hospital
- Jie Wu, Shengjing Hospital of China Medical University
- Jieyu You, Hunan Children's Hospital
- Lanlan Geng, Sitang Gong, Guangzhou Women and Children's Medical Center
- Lihong Shang, Xiaoli Xie, Chengdu Women's & Children's Central Hospital
- Li Zhu, Clinical Medical School of Maternal and Child Affiliated to Guizhou Medical University
- Xiaoqin Li, Zhengzhou Children's Hospital
- Xiwei Xu, Beijing Jing Du Children's Hospital
- Xuemei Zhong, Children's Hospital, Capital Institute of Pediatrics
- Ying Fang, The Children's Hospital of Xi’an City
- Yongli Fang, Jing Zhang, Beijing Children's Hospital, Capital Medical University
- Zailing Li, Peking University Third Hospital
- Zhongyue Li, Childen's Hospital of Chongqing Medical University
- Zhaoxia Wang, Shenzhen Children's Hospital
South Korean Centers Participating in the Survey
- Ben Kang, Kyungpook National University Children's Hospital, Daegu, Korea
- Byung-Ho Choe, Kyungpook National University Children's Hospital, Daegu, Korea
- Kwang Hae Choi, Yeungnam University Medical Center, Daegu, Korea
- Suk Jin Hong, Daegu Catholic University Medical Center, Daegu, Korea
- Hyo Jeong Jang, Keimyung University Dongsan Hospital, Daegu, Korea
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