key: cord-0806094-edpo9o7v
authors: Taylor, Richard; Mallon, Daniel
title: COVID-19 and Pediatric Gastroenterology
date: 2021-07-27
journal: Pediatr Clin North Am
DOI: 10.1016/j.pcl.2021.07.003
sha: 0291e96a898fcda9d732af4b86d4dbf24c56d306
doc_id: 806094
cord_uid: edpo9o7v

Pediatric gastroenterologists took on a variety of challenges during the COVID-19 pandemic, including learning about a new disease and how to recognize and manage it, prevent its spread among their patients and health professions colleagues, and make decisions about managing patients with chronic gastrointestinal and liver problems in light of the threat. They adapted their practice to accommodate drastically reduced in-person visits, adopting telehealth, and instituting new protocols to perform endoscopies safely. The workforce pipeline was also affected by the pandemic because of its impact on trainee education, clinical experience, research, and job searches.

The novel coronavirus, SARS CoV-2, responsible for the coronavirus disease (COVID- 19) was first recognized in Wuhan, China in December 2019 and rapidly spread. Globally, there have been more than 127 million cases with 2.8 million deaths with the United States contributing more than 30 million cases and 500 thousand deaths as of April 2021. The impact of this cannot be understated with far-reaching changes in the world and medicine. Our goal is to provide a review tailored to pediatric gastroenterologist that focuses on caring for patients with COVID-19, preventing the disease in patients with chronic gastrointestinal and liver disorders, and adapting to widespread changes to clinical practice and training.

In children and adolescents, COVID-19 generally presents similar to a viral upper respiratory infection with the most common presenting symptoms being cough (48.5%), pharyngeal erythema (46.2%), fever (41.5%), diarrhea (8.8%), fatigue (7.6%), rhinorrhea (7.6%), and vomiting (6.4%) 1 . When symptomatic, pediatric patients are more likely to have mild disease (53%) that can be managed in the outpatient setting 2 . A meta-analysis by Viner et al 3 showed children have a significantly lower susceptibility to COVID-19 infection with an odds ratio of 0.56 compared with adults. Saleh et al 4 specifically investigated hospitalized children with COVID-19 and found that the most common presentations were fever (95%), headache (60.3%), fatigue (57.8%), and shock (21.8%). Acute pancreatitis (1.5%) was the most common atypical presentation of COVID-19 in this study 4 . Common lab abnormalities in hospitalized patients with COVID-19 include leukopenia, lymphopenia, elevated inflammatory markers, and abnormal liver tests [4] [5] [6] . Mortality rates remain low in children with 0.17 per 100,000 or 0.48% of J o u r n a l P r e -p r o o f the estimated total mortality from all causes in a normal year 7 . Older children have a higher mortality rate than young children, however the rate is still low compared to adults 7 .

Pathophysiology SARS-CoV-2 is a positive-sense single-stranded RNA virus 8 . It enters target cells via interaction between the viral spike protein and angiotensin converting enzyme 2 (ACE-2) receptors. Injury is likely due to direct cytotoxic effect of the virus, dysregulation of the reninangiotensin-aldosterone system (RAAS), cell endothelial damage, thromboinflammation, and dysregulated immune response (Figure 1) 9 .

Gastrointestinal (GI) injury is multifactorial. There is a high prevalence of ACE-2 receptors in enterocytes with known viral replication in the GI tract given the presence of live virus in patients stool 9, 10 . There is also diffuse microvascular small-bowel injury and inflammation-mediated tissue damage of the stomach, duodenum, and rectum 9 . Hepatobiliary injury is also multifactorial and may be due to ACE-2 mediated entry of SARS-CoV-2 directly into cholangiocytes damaging the biliary ducts 9, 11 . While some series reported up to 37% of patients had abnormal liver tests 12 , a pooled data meta-analysis indicated no greater risk of abnormal transaminases or total bilirubin 13 . Drug-induced hepatic injury related to COVID-19 treatment is also possible. Some early reports of Remdesivir treatment for COVID-19 included increased transaminases and bilirubin 14 , but meta-analysis of multiple reports 15 and studies in the pediatric 16 and transplant populations 17, 18 found no increased risk of liver injury. Pancreatic injury is also multifactorial and hypothetically due to cytotoxicity of the virus via ACE-2 receptors in the pancreas, drug-induced injury, and damage secondary to the cytokine storm caused by immune dysregulation in severe infections 19 . Of note, pancreas injury secondary to SARS-CoV-2 is controversial, though the pathophysiology is plausible [19] [20] [21] . Of particular interest to pediatric gastroenterologist is the high prevalence of gastrointestinal manifestations which is the most common organ system involved 23 . The most common GI manifestations are abdominal pain, diarrhea, and nausea/vomiting 25 . These symptoms are secondary to inflammation along the GI tract with the ileum and colon most commonly effected 25 . In severe cases there can be bowel wall thickening causing luminal narrowing and obstruction. Fortunately, most children will have resolution of their manifestations with appropriate medical management, however rarely patients have required surgical resection 25 . Interestingly, when patients with severe abdominal pain underwent computed tomography (CT) imaging ~85% showed inflammatory bowel changes including marked terminal ileitis, inflammation of the cecum, and mesenteric fat stranding 25 . Mucosal hyperenhancement, fibrostenosis, and penetrating lesions were not seen. On histopathologic assessment of the surgically removed tissue there was noted to be marked transmural J o u r n a l P r e -p r o o f lymphocytic inflammation, venous microthrombi, arteritis, and necrotizing lymphadenitis which was distinct from chronic inflammatory bowel disease 25 .

Acute hepatitis and pancreatitis have also been linked to MIS-C. Previous studies in adults have shown as high as 43% of patients with MIS-C have hepatitis during their course 26 .

Patients with hepatitis were noted to have more severe disease with higher inflammatory cytokine levels, longer hospitalizations, and increased respiratory support 26 . Though long-term data is not currently available over 50% of patients had persistent AST and ALT elevation at 1 month follow up visits 26 . There is less literature on pancreatitis during MIS-C; however, adult studies have reported a 3% prevalence 23 .

Patients with inflammatory bowel disease (IBD) on immunosuppressive medication are at greater risk for infections. Co-morbidities are a risk factor for severe COVID-19 infection, so there is particular concern for worse outcomes in pediatric IBD patients. Fortunately, current pediatric data is encouraging that COVID-19 is well tolerated in this population 27 There is also no difference in severity of COVID-19 infection between patients with Crohn's Disease, Ulcerative Colitis, or unspecified IBD 27, 28 .

Mesalamine and chronic steroids confer an increased risk of COVID-19 infection with steroids conferring the highest risk 29-31 . Other risk factors associated with COVID-19 incidence J o u r n a l P r e -p r o o f and severity in a mixed population of adults and children were older age, male gender, and comorbities such as cardiovascular disease and diabetes 31 . Immunomodulators and biologic medications including infliximab and vedolizumab for IBD do not confer increased risk of COVID-19 infection or increased severity when contracted 31, 32 . The most common complication recognized in IBD patients was not related to COVID-19 specifically but delays in therapy or follow-up due to changes in hospital policies or parental concerns 28 . Patients should receive their regularly scheduled infusions during the pandemic as delay increases the risk for exacerbation 28 .

Interestingly, biologics may be protective against severe COVID-19 infection and many immunomodulators are currently under investigation as possible treatments for the aberrant inflammatory response caused by COVID-19 27 .

One of the most pressing issues for pediatric gastroenterologist is whether they should be recommending the COVID-19 vaccine to their patients with IBD. Multiple vaccines have been approved and have shown excellent efficacy and safety in the general population. 33 patients with liver disease, however they did show a higher observed incidence of infection than the estimated incidence in the population. Of note, their study reported 12% of their population as symptomatic for COVID-19 based on exposures, however only 0.5% of patients had a confirmed case via testing causing this data to be difficult to interpret. Regardless of the potential increased risk, treating patients with pre-existing liver disease is further complicated by the hepatotoxicity of many of the medications used to treat COVID-19 9, 11 . The adult data supports cirrhosis as a risk factor for severe disease, however again the data in pediatrics is unclear 38, 39 .When investigating autoimmune hepatitis (AIH) as compared to other etiologies of liver disease there was no difference in rate of severe disease 40 . Similar to IBD, immunosuppression with biologic agents was not a risk factor for severe disease secondary to COVID-19 for patients with AIH 40 .

Similar to other chronic liver diseases MAFLD, formerly known as nonalcoholic fatty liver disease, has been shown to have higher risk of disease progression and longer viral shedding as compared to patients without MAFLD though specific pediatric data is lacking 41 .

Obesity, diabetes, and hypertension are all prominent risk factors for severe COVID-19 infection and are common co-morbidities in patients with MAFLD 11 . Patients with MAFLD may have more severe COVID-19 infections due to inflammation-suppressing M2 macrophages activation J o u r n a l P r e -p r o o f rather than M1 macrophages, however this is hypothetical 11 . Pediatric gastroenterologist should be prepared to see a to higher prevalence and worsening severity of MAFLD as the COVID-19 pandemic has caused a significant decrease in activity for many children which could worsen patients' obesity 42 . It is vital for pediatric gastroenterologist to help families identify safe effective ways to increase physical activity to help delay and potentially reverse the progression of MAFLD.

The risk of infection with SARS-CoV-2 in liver transplant patients is unclear 11, 38 . The literature is limited, and results are mixed. Large adult registry data around the world have shown no increased incidence of infection, but higher mortality rates 11 . Colmenero et al 43 reported the opposite of this in their prospective cohort study with a higher incidence of COVID- 19 infections, but lower mortality rate as compared to matched members of the general population. Two case reports of COVID-19 and MIS-C in pediatric liver transplant recipients had poor outcomes 44, 45 , however the observational cohort study by Kehar et al 38 specifically assessing pediatric liver transplant patients showed improved outcomes as compared to patients with chronic liver disease. Consistent with data in other diseases, immunosuppression has not been shown to be a risk factor for increased severity of COVID-19 infection 11, 43 There has been a decrease in all solid organ transplants since the start of the COVID-19 pandemic 46 . 

There is no apparent increased risk of COVID-19 infection due to IBD, but oral corticosteroids do increase risk of severe COVID-19. There is no difference in disease severity between UC, Crohn's, or unspecified IBD. Immunosuppression is safe and regimens should not be changed prophylactically, except to minimize steroid use. COVID-19 vaccine is strongly recommended for IBD.

There is significantly increased risk of COVID-19 infection, particularly patients with MAFLD. The treatment of COVID-19 infection is complicated by the hepatotoxic effects of medications. The incidence of MAFLD likely increased during the pandemic due to decreased exercise.

There is Increased risk of COVID-19 infection, however it is less than patients with CLD. Immunosuppression is safe and regimens should not be changed prophylactically, except to minimize steroid use. Vaccination is recommended for recipients, candidates, and close contacts.

When the pandemic was identified and advice to reduce in-person visits to healthcare facilities and postpone elective surgical procedures, it had a large impact on pediatric gastroenterology practices. Outpatient visits dropped 8, 53 , and most endoscopy came to a halt 54 .

Pediatric gastroenterologists considered the risk of transmission of SARS CoV-2 to patients, staff and themselves, the risk of delayed diagnosis for new patients, jeopardized health of children with chronic disease due to delays in follow up care, medication or dietary adherence, reduced clinical opportunities for trainees and the financial impact of reduced visits and endoscopies. Concerns about delays in diagnosis were realized in reports of severe illness and deaths due to diabetic ketoacidosis, pyloric stenosis, sepsis and cancer in children presenting to the hospital after delays attributed to fear of COVID-19 and reduced access to care 55, 56 . Delays in presentation were suspected to contribute to an increase the rate of complicated appendicitis in J o u r n a l P r e -p r o o f more than one series [56] [57] [58] [59] . A study of a large sample of emergency departments in the US revealed a drop in pediatric visits by up to 72% compared to the same week one year prior 60 .

Comparing the same 3-month period, March to June, there was a 22% decline in visits for serious conditions including appendicitis and intussusception, and a 62% drop in visits for abdominal pain 60 . Patients were not visiting gastroenterology clinic either; the largest pediatric GI practice in Iowa saw 20% and 90% reductions in face-to-face encounters in March and April 2020, respectively, compared to 2019 53 . That report and others highlighted the pivot to telehealth to see patients 53, 61, 62 .

Telehealth utilization rose in response to the pandemic 63 , facilitated by the relaxation of some regulatory requirements and affirmations of reimbursement by public and private payers 64 .

Pediatric gastroenterology practices utilized existing and new technology via electronic health records, mobile and computer teleconferencing applications. A timely publication offered guidance specifically to pediatric gastroenterologists adopting telehealth 65 . A few centers have reported successful experiences using telehealth, including adapting multidisciplinary subspecialized disease based clinics 66 , and an approach to triaging referrals as e-consults, telehealth or in-person visits 67 . Several studies have demonstrated the utility of telehealth for pediatric primary and subspecialty care 68, 69 , but inequities in utilization and technology have been seen and merit addressing 70, 71 .

The future of telehealth beyond the pandemic is bright, but some uncertainty remains.

According to a survey of large employers, 53% of employers plan to implement more virtual care solutions for their health plans 72 . The increased access to coverage for telehealth for Medicare beneficiaries has depended on a temporary waiver during the public health emergency With the reduction in endoscopic procedures, outpatient visits and hospital admissions, the opportunities for typical clinical training of fellows were diminished during the first several months of the pandemic 61, 79 . A survey of program directors revealed that endoscopy and typical outpatient clinical experiences were drastically reduced, but fellows were included with the rapid adoption of telehealth for outpatient visits 61 . Fellows' research activities were curtailed due to lack of access to research subjects and to the lab. Indeed, many fellows altered their research methodology or refocused on an alternative project. When fellows were surveyed, large proportions reported subjective negative impact on clinical (52%), research (46%) and procedural confidence (41%) 79 . A small but important proportion of fellows graduating in the summer of 2020 reported that their post-fellowship employment contracts were altered or rescinded due to hiring freezes attributed to the pandemic. Fellows in their first and second of three-year fellowships reported high levels of concern in finding a job after graduation.

Pediatric gastroenterologists took on a variety of challenges during the COVID-19

pandemic, including learning about a new disease and how to recognize and manage it, prevent its spread among their patients and health professions colleagues, and make decisions about J o u r n a l P r e -p r o o f managing patients with chronic gastrointestinal and liver problems considering the threat (Table   1 ). They adapted their practice to accommodate drastically reduced in-person visits, adopting telehealth, and instituting new protocols to perform endoscopies safely. The workforce pipeline was also affected by the pandemic because of its impact on trainee education, clinical experience, research, and job searches.

Driven by vaccinations against COVID-19, the rate of infections in the United States is declining 80 , and public health measures such as mask mandates and restrictions on public gatherings are being lifted. As patients have returned to clinics, hospitals have filled again and procedures have resumed, pediatric gastroenterologists will consider ways to integrate telehealth into future practice, address questions about vaccinating and possibly revaccinating patients and continue to consider COVID-19 as a potential cause of gastrointestinal illness.

 COVID-19 infection and MIS-C often have GI manifestations that can be severe and the initial presenting symptoms. 

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