The infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19). The novel coronavirus is a part of the family Coronaviridae and was first identified in the context of a respiratory disease outbreak in Wuhan, China, in December 2019. In late January 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a global health emergency, then in March the global pandemic was recognized.
SARS-CoV-2 is a positive-sense single-stranded RNA virus in the Betacoronavirus genus and phylogenetically connected (88-89% similarity) with the two similar SARS coronaviruses, namely BAT-SL-CoVZC45 and BAT-SL-COVZXC21(1). Coronaviruses can mutate quickly and recombine, resulting in new coronaviruses with different transmission profiles (SARS-CoV – in the year 2002, and MERS-CoV – in the year 2012). The virus enters the human host cell via angiotensin-2, the main receptor, expressed on the outer membrane of cells specific of the small intestine, kidneys, testicles etc.
COVID-19 has affected a large number of people across the globe, being reported in approximately 200 countries and territories. Approximately 73 million cases have been reported worldwide since April 2020 and to this date(1).
In spite of the large outbreaks all over the world, the rate of hospital admission among pediatric patients was much lower compared to that of adults. According to the Centers for Disease Control and Prevention (CDC) in the United States, children under 18 years old account for approximately 10 to 12 percent of laboratory-confirmed cases; out of these, 1.8% are aged 0-4 years old and 8.3% are aged 5-17 years old. Both sexes were similarly affected, with 40% of the children remaining asymptomatic, 51% presenting mild symptoms, and only 6% were reported to have severe forms. It was noted that toddlers develop severe forms of the disease at a higher rate than older children. As far as age distribution is concerned, approximately 11% of toddlers presented with severe forms of the disease, compared to 7% of children aged 1 to 5 years old, 4% in the 6-10 years old group, 4% in 11-15-year-olds and 3% in 16-18-year-olds(3).
The virus can be transmitted via Flügge’s droplets produced during exhalation when the infected person speaks, coughs, sneezes etc. The incubation period from virus exposure to the onset of symptoms is estimated around 2-14 days(2). Airborne transmission may be possible under specific circumstances, such as performing aerosol generating procedures or support treatments (endotracheal intubation, digestive endoscopy, bronchoscopy, aspiration, administration of nebulizer treatment, manual ventilation, tracheostomy etc.).
Although the clinical symptomatology in adults is predominantly respiratory, in pediatric patients it is diverse. The majority of symptoms in children are common respiratory ones: fever (50%), coughing (38%), and in mild forms of the disease the children can be asymptomatic(9).
The gastrointestinal symptomatology is frequent among pediatric patients diagnosed with COVID-19 and had an increased prevalence in the subsequent phase of the epidemic from China. SARS-CoV-2 penetrates the gastrointestinal epithelial cells, therefore the feces of coronavirus infected patients are potentially infectious(2). In 29 studies (6,064 cases) that reported gastrointestinal symptoms in COVID-19 patients, the common prevalence of digestive symptoms was 15%, the most frequent including nausea, vomiting, diarrhea and anorexia. The authors report that approximately 10% of COVID-19 patients present with gastrointestinal symptoms and with no respiratory manifestations.
Diarrhea was the most frequently encountered symptom among children, with an average duration of 5 days, and was noticed both before and after making the diagnosis. Vomiting and abdominal pain are also present among children infected with the novel coronavirus (66.7%)(5).
The influence of SARS-CoV-2 infection
in pediatric digestive pathology
The initial reports concerning COVID-19 focused on respiratory symptoms. However, subsequent data showed that the infection can affect other systems, including the gastrointestinal system. In June 2020, the case definition was updated in Romania, as follows: any child under the age of 16 and presenting with gastrointestinal manifestations (diarrhea, vomiting) not associated with their food intake shall be deeded suspect of SARS-CoV-2 infection(4).
The connection between inflammatory bowel disease (IBD) and the SARS-CoV-2 infection is represented by the angiotensin-converting enzyme 2 (ACE2) necessary for the virus to bind to and enter into target cell. ACE2 is mainly attached to the membrane of type II alveolar cells, but it is also encountered in small bowel enterocytes, vascular endothelial cells and in arterial smooth muscle cells. The expression of the angiotensin-converting enzyme 2 increases in intestinal inflammatory pathology, particularly in the case of patients with Crohn’s disease, so it would appear that IBD favors the entry of the virus into the human body(5). Although there is a higher susceptibility in IBD, as far as frequency is concerned, no increase in the number of cases of infection with the novel coronavirus was noted in patients with IBD compared to the general population(6).
The North-American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) recommends general practitioners, whenever possible, to closely monitor the evolution of inflammatory bowel disease and to use telemedicine based on criteria individualized and adapted for each patient, as well as to avoid exposure to the hospital environment when patients experience controlled forms of the disease, without exacerbations. It is important that patients and their next of kin understand the importance of treatment in inflammatory bowel diseases and that they do not disrupt the treatment without medical advice during the pandemic. IBD patients will continue to be treated and monitored in line with individualized protocols to minimize the risk of developing complications. This risk is higher compared to the risk of disease caused by SARS-CoV-2(6).
Quantifying immediate and long-term risks is a difficult task in the case of immunosuppressed patients. The therapeutic approach is based on a careful analysis of the risk-benefit report, in this case the risk of the SARS-CoV-2 infection with a potential IBD relapse (or flare-up). The guidelines refer to the main drugs used in pediatric IBD treatment, as follows:
According to current guidelines, mesalazine and sulfasalazine do not increase the risk of infection with SARS-CoV-2 and the patients under treatment with 5-aminosalicylates must not stop their treatment or decrease their doses to prevent the infection with the novel coronavirus. In the same time, patients confirmed positive for the infection with SARS-CoV-2 (symptomatic or asymptomatic) may continue their treatment with 5-aminosalicylates(6).
Prednisone in doses exceeding 20 mg/day increases the risk of infection with SARS-CoV-2, which is why it is recommended to decrease the dose; if confirmed positive, patients under treatment with prednisone in doses higher than 20 mg/day should gradually decrease the doses(6).
Azathioprine, methotrexate, 6-mercaptopurine (6-MP)
Patients under treatment with azathioprine, 6-MP or methotrexate must not stop their treatment or decrease their recommended doses if they are not infected with SARS-CoV-2; however, it is recommended to stop the treatment upon confirmation of the SARS-CoV-2 infection and resuming the treatment once the RT-PCR test result is negative(6).
Patients under treatment with anti-TNF (tumoral necrosis factor) must not stop the treatment administration to prevent the infection with SARS-CoV-2; it is recommended to postpone the biological treatment for 14 days after receiving a positive test result and resuming it once the PCR nasopharyngeal swab test for SARS-CoV-2 comes out negative(6).
Chronic liver diseases in the context
of the pandemic
Patients with severe COVID-19 develop facial hyperpigmentation and dull skin after recovery. Liver injury during COVID-19 is mainly responsible for these special manifestations. There are three possible mechanisms: (a) iron in the damaged liver drains into blood vessels; the blood with high iron level can lead to a hyperpigmentation of the face; (b) estrogen cannot be metabolized in the damaged liver and the excess of estrogen in the blood eventually causes an increases in conversion of tyrosine to melanin; (c) when liver function is impaired, adrenocortical function is hypoactive and melanocyte stimulating hormone increases(7).
Modifications in liver function tests were noticed in 14% to 58% of cases (hepatic cytolysis syndrome, mild hyperbilirubinemia). Elevated AST levels along with hypoalbuminemia and thrombocytopenia are considered a marker for the severity of the SARS-CoV-2 infection. Severe liver damage is rare in children infected with the novel coronavirus(8).
Guidelines recommend monitoring patients with chronic liver disease in local centers and encourage telemedicine when the patient has a good clinical status in order to reduce the risk of in-hospital SARS-CoV-2 transmission. This helps avoid overcrowding in regional centers, on the one hand, and creates the premises for protecting the medical staff, on the other hand(9).
The clinical studies undertaken have shown that patients with viral hepatitis do not present an additional risk for developing severe forms of COVID-19. In the case of autoimmune hepatitis, it is not recommended to reduce the immunosuppressive therapy, excepting the cases with severe forms of SARS-CoV-2 infection and multiple organ failure(8).
The recommendation for patients with compensated liver cirrhosis is to delay the screening for esophageal varices with minimum exposure to in-hospital environments and using telemedicine as much as possible, without endangering the life of patients. For patients with decompensated liver cirrhosis it is recommended to continue the rigorous prophylaxis of spontaneous bacterial peritonitis (norfloxacin/trimethoprim-sulfamethoxazole) and portal encephalopathy. Testing for the SARS-CoV-2 infection must be conducted in all cases of acute decompensations or acute liver failure. Guidelines reiterate the importance of pneumococcal and flu vaccine. This helps avoid the aggravation of symptomatology in the case of respiratory infections and, implicitly, a potential hospital admission(9).
Liver transplant in the context
The COVID-19 pandemic significantly reduced the number of organ donors. As a result of this phenomenon, the criteria for liver transplant have been reconsidered. Transplant lists were limited only to patients with severe short-term prognosis, liver failure and cell hepatocellular carcinoma(8,9).
The European Association for the Study of the Liver (EASLD) together with the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommend the routine testing for both the donor and the recipient before performing the transplant. It is mandatory that both the informed consent forms for the transplant and the pre- and post-procedure consent forms mention the risk of nosocomial infection with SARS-CoV-2(8).
The impact of the SARS-CoV-2 infection
on endoscopic investigations
The endoscopy unit is a high-risk environment for the transmission of SARS-CoV-2 infection because of the aerosols, the possible virulence of digestive secretions, as well as the relative small distance between the patient and the medical staff during the investigation, both for upper and lower digestive endoscopy. Another factor that increases the risk of generating and spreading virulent particles that must be taken into consideration during the procedure is the need for deep sedation in the case of young pediatric patients by the anesthesiologist(10).
The studies conducted in Great Britain detected a significant decrease during the first peak of the pandemic. Thus, in the whole country, approximately 1,700 endoscopies were carried out during a one-week interval, compared to 35,000 before the pandemic(11).
From an epidemiological point of view, the digestive pathology in children is substantially different from that of adult patients, which can influence the need to perform urgent endoscopic investigations. Thus, children present with a higher severity in the case of an inflammatory bowel disease, they have a higher incidence of foreign body ingestion, congenital malformations requiring endoscopic therapy, and they need devices for enteral feeding (PEG – percutaneous endoscopic gastrostomy, nasal-jejunal feeding tube)(11).
In the context of the global pandemic, the number of endoscopies dropped significantly compared to the average in previous years; elective cases were postponed, while pediatric emergencies were taken in immediately, with no delay to the procedure for patients who are suspected or confirmed positive for the SARS-CoV-2 infection.
Risk layering for endoscopic procedures that need to be conducted urgently (within maximum 24 hours):
Digestive hemorrhages that are life-threatening for the patient.
Foreign body ingestion classified by NASPGHAN guidelines:
immediate (maximum 2 hours as of ingestion) – round batteries located in the esophagus or in the stomach if the patient is symptomatic, has an anatomical anomaly or also swallowed a magnet simultaneously; food bolus impacted in the esophagus producing symptomatology (pain, sialorrhea); sharp/cutting objects (esophagus, stomach, proximal duodenum – even in the absence of symptomatology);
urgent (within 24 hours) – blunt objects impacted in the esophagus (including coins); food bolus impacted in the esophagus even in the absence of symptomatology); unsharpened objects with a diameter larger than 2.5 cm and longer than 6 cm or which produce symptoms and are located in the stomach; cylinder battery impacted in the esophagus; magnets that can be removed endoscopically.
Bowel obstruction (requiring endoscopic therapy).
Decompression of a volvulus.
Assessment of corrosive substance ingestion (with present symptomatology – sialorrhea, dysphagia).
Postponing the procedures is a challenge for the pediatric gastroenterologist, as it requires weighing all the options and risks of the endoscopy in view of a favorable management, without endangering the patient’s life.
Foreign body ingestion:
coins/blunt foreign body located in the stomach – can be monitored in an outpatient regime, with follow-up radiology reevaluation after 4 weeks;
round batteries with a diameter larger than 2 cm located in the stomach (radiology monitoring and removal if they remain in the same place 48 hours later); cylinder batteries located in the stomach, which can be monitored in an outpatient regime, and follow-up radiology reevaluation after 7-14 days if they did not pass in the meantime.
Endoscopic monitoring of esophageal varices banding.
Moderate dysphagia (does not tolerate the ingestion of solids).
Initiating/replacing nutritional support (PEG).
Recommendations for protective equipment
Considering the fact that the majority of pediatric patients are asymptomatic or present with minor symptomatology and the potential for transmitting the SARS-CoV-2, the Centers for Disease Control and Prevention (CDC) recommends that all endoscopic procedures be conducted in a negative pressure room regardless of the patient’s risk layering. In Romania, these special rooms are currently not available in pediatric gastroenterology centers. The medical staff must include only the strictly necessary people and must be well-trained in the use of protective equipment: N95, N99, FFP2/FFP3 protection masks, protective goggles, face shield, hair net, double gloves, waterproof single-use gown/overalls with long sleeves, single-use shoe covers. During lower digestive endoscopies it is preferable to use N95 type masks due to fecal matter particles potentially producing aerosols via the colonoscopy biopsy shaft. Surgical masks only block large particles and are ineffective for particles smaller than 5 µm(13).
CDC recommends the following steps for putting on the equipment: single use shoe covers – hair net – protective gown – respiratory mask – goggles + face shield – gloves. Taking off the equipment is also essential to avoid contaminating the staff and adjacent surfaces: the first pair of gloves – goggles and face shield – gown – respiratory mask – gown – single use shoe covers – the last pair of gloves. The protective equipment must not be removed before finishing up the procedure, and the mask must cover the nose and mouth throughout the investigation. The next of kin are not allowed access into the endoscopy room except in absolutely exceptional cases, and they will wear a mask and will be informed about the risk to which they are exposing themselves(13).
While performing the procedure, it is recommended to restrict the access of medical staff as much as possible and to keep the necessary staff to a minimum, staff rotation, the access into the endoscopy room after intubating the patients, and avoiding to introduce personal effects in the endoscopy room (mandatory subsequent disinfection). The endoscopic techniques being used have to be adapted in order to limit the production of aerosols (minimizing the use of air/CO2). While taking biopsies, it is recommended to use aspiration, as it can reduce the production of aerosols.
In case of patients suspected of COVID-19, the unit where the procedure is performed must provide a pre- and post-procedure room in order to avoid contact, as well as spreading the virus to other patients.
Staggering the schedules for endoscopies is the most important in order to adequately ventilate and clean the room and the medical devices used. The children’s next of kin are urged to inform the medical staff if the children present with any symptoms specific to the SARS-CoV-2 infection in the 7-14 days following the procedure.
The COVID-19 pandemic has substantially changed how endoscopies are performed, given that the SARS-CoV-2 infection can also be localized in the digestive tract and can be transmitted to the medical staff during aerosol generating digestive endoscopy procedures. As the pandemic evolves, guidelines are constantly changing in order to streamline the medical services, as well as to avoid patients and the medical staff becoming infected with SARS-CoV-2.