Intussusception and COVID-19 in Children: A Systematic Review and Meta-Analysis

Background: Intussusception (ISN) post-COVID-19 infection in children is rare but can occur. SARS-CoV-2 may play a role in the pathogenesis of ISN and trigger immune activation and mesenteric adenitis, which predispose peristaltic activity to “telescope” a proximal bowel segment into the distal bowel lumen. Objectives: To estimate the prevalence of SARS-CoV-2 infection in ISN children and analyze the demographic parameters, clinical characteristics and treatment outcomes in ISN pediatric patients with COVID-19 illness. Methods: We performed this systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Studies reporting on the incidence of ISN post-SARS-CoV-2 infection in children, published from 1 December 2019 until 1 October 2022, in PROQUEST, MEDLINE, EMBASE, PUBMED, CINAHL, WILEY ONLINE LIBRARY, SCOPUS and NATURE, with a restriction to articles available in the English language, were included. Results: Of the 169 papers that were identified, 34 articles were included in the systematic review and meta-analysis (28 case report, 5 cohort and 1 case-series studies). Studies involving 64 ISN patients with confirmed COVID-19 (all patients were children) were analyzed. The overall pooled proportions of the ISN patients who had PCR-confirmed SARS-CoV-2 infection was 0.06% (95% CI 0.03 to 0.09, n = 1790, four studies, I2 0%, p = 0.64), while 0.07% (95% CI 0.03 to 0.12, n = 1552, three studies, I2 0%, p = 0.47) had success to ISN pneumatic, hydrostatic and surgical reduction treatment and 0.04% (95% CI 0.00 to 0.09, n = 923, two studies, I2 0%, p = 0.97) had failure to ISN pneumatic, hydrostatic and surgical reduction treatment. The median patient age ranged from 1 to 132 months across studies, and most of the patients were in the 1–12 month age group (n = 32, 50%), p = 0.001. The majority of the patients were male (n = 41, 64.1%, p = 0.000) and belonged to White (Caucasian) (n = 25, 39.1%), Hispanic (n = 13, 20.3%) and Asian (n = 5, 7.8%) ethnicity, p = 0.000. The reported ISN classifications by location were mostly ileocolic (n = 35, 54.7%), and few children experienced ileo-ileal ISN (n = 4, 6.2%), p = 0.001. The most common symptoms from ISN were vomiting (n = 36, 56.2%), abdominal pain (n = 29, 45.3%), red currant jelly stools (n = 25, 39.1%) and blood in stool (n = 15, 23.4%). Half of the patients never had any medical comorbidities (n = 32, 50%), p = 0.036. The approaches and treatments commonly used to manage ISN included surgical reduction of the ISN (n = 17, 26.6%), pneumatic reduction of the ISN (n = 13, 20.2%), antibiotics (n = 12, 18.7%), hydrostatic reduction of the ISN (n = 11, 17.2%), laparotomy (n = 10, 15.6%), intravenous fluids (n = 8, 12.5%) and surgical resection (n = 5, 7.8%), p = 0.051. ISN was recurrent in two cases only (n = 2, 3.1%). The patients experienced failure to pneumatic (n = 7, 10.9%), hydrostatic (n = 6, 9.4%) and surgical (n = 1, 1.5%) ISN treatment, p = 0.002. The odds ratios of death were significantly higher in patients with a female gender (OR 1.13, 95% CI 0.31–0.79, p = 0.045), Asian ethnicity (OR 0.38, 95% CI 0.28–0.48, p < 0.001), failure to pneumatic or surgical ISN reduction treatment (OR 0.11, 95% CI 0.05–0.21, p = 0.036), admission to ICU (OR 0.71, 95% CI 0.83–1.18, p = 0.03), intubation and placement of mechanical ventilation (OR 0.68, 95% CI 0.51–1.41, p = 0.01) or suffering from ARDS (OR 0.88, 95% CI 0.93–1.88, p = 0.01) compared to those who survived. Conclusion: Children with SARS-CoV-2 infection are at low risk to develop ISN. A female gender, Asian ethnicity, failure to ISN reduction treatment (pneumatic or surgical), admission to ICU, mechanical ventilation and suffering from ARDS were significantly associated with death following ISN in pediatric COVID-19 patients.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children may be underreported, as most cases of coronavirus disease 2019  in the pediatric population are mild or asymptomatic, but a small number of individuals may develop severe disease, requiring intensive care admission and/or mechanical ventilation [1]. In addition to the respiratory system, SARS-CoV-2 also infects the gastrointestinal system [2]. Some digestive tract symptoms, such diarrhea, vomiting, loss of appetite, stomach upset or abdominal pain, occur with or before respiratory symptoms in patients with COVID-19, with the highest incidence in pediatric age [3]. Very few sporadic cases of intussusception (ISN) in SARS-CoV-2-infected children have been reported worldwide [4][5][6][7]. ISN, defined as the invagination (telescoping) of a part of the intestine into itself, is a rare condition and considered to be the most common abdominal emergency in early childhood, particularly in children younger than two years of age [8,9]. ISN typically presents between 6 and 36 months of age, and it is the most common cause of intestinal obstruction in this age group [8]. In most episodes, ISN occurs in otherwise healthy and well-nourished children [10]. An increasing body of evidence suggests that viral triggers may play a role in the pathogenesis of ISN, and many common viral infections are associated with ISN, including adenovirus, rotavirus and human herpes simplex virus [11,12]. Children are thought to be susceptible to high peristaltic activity to "telescope" a proximal bowel segment into the distal bowel lumen due to the occurrence of local immune activation and mesenteric Children 2022, 9,1745 3 of 32 adenitis [13]. Refractory abdominal pain or mass, vomiting, bloody stool or red currant jelly stools, and lethargy are common symptoms of ISN [13]. Ultrasound or computerized tomography of the abdomen are used for diagnosis (see Figure 1). presents between 6 and 36 months of age, and it is the most common cause of intestinal obstruction in this age group [8]. In most episodes, ISN occurs in otherwise healthy and well-nourished children [10]. An increasing body of evidence suggests that viral triggers may play a role in the pathogenesis of ISN, and many common viral infections are associated with ISN, including adenovirus, rotavirus and human herpes simplex virus [11,12]. Children are thought to be susceptible to high peristaltic activity to "telescope" a proximal bowel segment into the distal bowel lumen due to the occurrence of local immune activation and mesenteric adenitis [13]. Refractory abdominal pain or mass, vomiting, bloody stool or red currant jelly stools, and lethargy are common symptoms of ISN [13]. Ultrasound or computerized tomography of the abdomen are used for diagnosis (see Figure 1).

Figure 1.
Graphical representation of ISN in children. ISN classically presents in an infant or toddler with (1) sudden onset of intermittent, severe, and progressive abdominal pain and palpable sausage-shaped abdominal mass, and/or (2) red currant jelly stool. ISN may possibly be due to (3) lead points (such as intestinal polyps or Meckel diverticulum). ISN refers to (4) the invagination (telescoping) of a part of the intestine into a more distal segment (proximal segment is known as the intussusceptum and the distal segment into which it telescopes is known as the intussuscipiens). Radiography findings may reveal a (5) lack of perfusion in the intussusceptum, indicating the development of ischemia.
With the nonavailability of comprehensive and updated systematic reviews focusing on the co-occurrence of those two medical conditions, we aimed to estimate the prevalence of ISN in pediatric COVID-19 children and analyze the demographic parameters, clinical characteristics and treatment outcomes in ISN patients with pediatric COVID-19 illness, with larger and better-quality data. Because ISN is a very rare phenomenon in adults and occurs mostly in children, the relative odds of ISN coexisting in adult COVID-19 patients was not included in the meta-analysis. We expect our review to provide clinicians with a  (1) sudden onset of intermittent, severe, and progressive abdominal pain and palpable sausageshaped abdominal mass, and/or (2) red currant jelly stool. ISN may possibly be due to (3) lead points (such as intestinal polyps or Meckel diverticulum). ISN refers to (4) the invagination (telescoping) of a part of the intestine into a more distal segment (proximal segment is known as the intussusceptum and the distal segment into which it telescopes is known as the intussuscipiens). Radiography findings may reveal a (5) lack of perfusion in the intussusceptum, indicating the development of ischemia.
With the nonavailability of comprehensive and updated systematic reviews focusing on the co-occurrence of those two medical conditions, we aimed to estimate the prevalence of ISN in pediatric COVID-19 children and analyze the demographic parameters, clinical characteristics and treatment outcomes in ISN patients with pediatric COVID-19 illness, with larger and better-quality data. Because ISN is a very rare phenomenon in adults and occurs mostly in children, the relative odds of ISN coexisting in adult COVID-19 patients was not included in the meta-analysis. We expect our review to provide clinicians with a thorough understanding of the infrequent concurrent occurrence of those two medical conditions in children.

Aim of the Study
This systematic review and meta-analysis aimed to estimate the prevalence of ISN in COVID-19 children and analyze the demographic parameters, clinical characteristics and treatment outcomes in ISN children with COVID-19 illness.

Design
We performed this systematic review following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) [14]. We The following different keywords were combined: ("COVID-19" OR "SARS-CoV-2" OR "Severe acute Respiratory Syndrome Coronavirus 2" OR "Coronavirus Disease 2019" OR "2019 novel coronavirus") AND ("children" OR "child" OR "paediatric" OR "pediatric" OR "infant" OR "toddler" OR "adolescent" OR "newborn") AND ("intussusception" OR "intestinal obstruction" OR "intestinal invagination"). Articles discussing and reporting the occurrence of ISN in children infected with COVID-19 were selected based on the title and abstract.

Inclusion-Exclusion Criteria
The eligible studies were included based on the following inclusion criteria: (1) published case reports, case-series and cohort studies that focused on COVID-19 in ISN patients that included children as a population of interest; (2) studies of an experimental or observational design reporting the incidence of SARS-CoV-2 infection in pediatric patients with ISN. The exclusion criteria included: (1) editorials, commentaries, reviews and meta-analyses; (2) studies that reported ISN in children with negative SARS-CoV-2 polymerase chain reaction (PCR) tests; (3) studies that reported ISN in adult COVID-19 patients.

Data Extraction
The screening of the papers was performed independently by six reviewers (Saad Alhumaid, Zainab Al Alawi, Abdulrahman A. Alnaim, Mohammed A. Al Ghamdi, Muneera Alabdulqader and Khalid Al Noaim) by screening the titles with abstracts using the selection criteria. Disagreements in the study selection after the full-text screening were discussed; if agreement could not be reached, a third reviewer was involved. We categorized articles as case report, case-series, clinical trials or cohort studies. The following data were extracted from the selected studies: authors; publication year; study location; study design and setting; age; proportion of male patients; patient ethnicity; medical comorbidities; total number of patients and number of ISN patients with positive SARS-CoV-2; ISN classification by location; symptoms from ISN; abnormal laboratory indicators; radiological imaging findings; if patient was admitted to the intensive care unit (ICU), placed on mechanical ventilation and/or suffered acute respiratory distress syndrome (ARDS); treatment given after ISN; if failure of pneumatic, hydrostatic or surgical reduction in patients with ISN occurred; if ISN was recurrent; assessment of study risk of bias; and final treatment outcome (survived or died); and they are noted in Table 1.

Quality Assessment
Two tools were used appropriately to assess the quality of the studies included in this review: (1) Newcastle-Ottawa Scale (NOS) to evaluate the cohort studies (scoring criteria: >7 scores = high-quality, 5-7 scores = moderate quality and <5 scores = low quality) [45]; (2) modified NOS to evaluate the case report and case-series studies (scoring criteria: 5 criteria fulfilled = good, 4 criteria fulfilled = moderate and 3 criteria fulfilled = low) [46]. A quality assessment was conducted by six co-authors (Koblan M. Al mutared, Yameen Ali Almatawah, Ahmed Tawffeq AlOmran and Sarah Mahmoud Al HajjiMohammed), who separately evaluated the possibility of bias using these two tools.

Data Analysis
We examined primarily the proportion of confirmed SARS-CoV-2 infection in patients with ISN. This proportion was further classified based on the success or failure of pneumatic, hydrostatic or surgical treatment to reduce ISN. A hydrostatic or pneumatic reduction failure to ISN was defined as ISN that could not be reduced using, most commonly, a fluoroscopic guide with hydrostatic (saline or contrast) or pneumatic (air) enema [47]. A surgical reduction failure to ISN was defined as ISN that could not be reduced using an operative intervention [47]. A recurrent ISN was defined as the recurrence of ISN after pneumatic, hydrostatic or surgical reduction (occurrence of abdominal pain and the radiologic appearance of an intussuscepted segment) [48]. Nonrecurrent ISN was defined as the cases that were successfully reduced after pneumatic or hydrostatic intervention or surgery without recurrence [48]. Because all of these data were continuous and dichotomous, these data are presented as numbers (percentages) and odds ratios (ORs) for estimating the point estimate, along with 95% confidence intervals (CIs). For prevalence of SARS-CoV-2 infection in ISN children, pooled effect size was illustrated using a forest plot; and to produce wider CIs than a fixed effect model, we used a random effects with the DerSimoniane-Laird model [49]. The Cochran's test for chi-squared (χ 2 ) expressed as the Higgins (I 2 ) were used to measure the statistical heterogeneity [50]. The degrees of heterogeneity were categorized based on the calculated I 2 values: (not significant: 0-<40%; moderate: 30-60%; substantial: 50-90%; and significant: 75-100%) [51]. Univariate and multivariable logistic regression analyses were used to estimate the odds ratios (ORs) and 95% CIs of the association of each demographic parameter and clinical variable with the treatment outcomes (i.e., survived or died) of ISN patients with SARS-CoV-2 infection. All p-values were based on two-sided tests, and significance was set at a p-value less than 0.05. We used R version 4.1.0 with the packages finalfit and forestplot for all statistical analyses.
Twenty-seven studies were deemed to have high methodological quality and two moderate methodological quality (Table 1). were assessed using the NOS: 4 studies were found to be moderate-quality studies (i.e., NOS scores between 5 and 7) and 1 study demonstrated a relatively high quality (i.e., NOS scores > 7). All case reports and case-series studies were assessed for bias using the modified NOS. Twenty-seven studies were deemed to have high methodological quality and two moderate methodological quality (Table 1).

Discussion
In this small systematic review and meta-analysis, we included 64 pediatric patients with PCR-confirmed SARS-CoV-2 infection from 34 observational studies to estimate the incidence of ISN in children with COVID-19. Linking between COVID-19 and ISN and establishing the relationship between them may help avoid diagnostic delays and allow for the development of more specific and efficient ways of ISN prevention and therapy. As expected, the overall incidence of ISN in pediatric patients infected with SARS-CoV-2 was very low (0.06%). The Incidence of ISN in pediatric COVID-19 patients who had a failure to pneumatic, hydrostatic or surgical reduction treatment compared to ISN patients with COVID-19 in whom intestinal obstruction was reduced successfully with pneumatic, hydrostatic or surgical interventions was even almost twofold lower in this group of ISN patients (0.04% vs. 0.07%). ISN is a rare form of intestinal obstruction in which a segment of the bowel prolapses into a more distal portion [52]. It can be argued that the prevalence of ISN in the pediatric population decreased during the COVID-19 pandemic, an issue that can be linked to COVID-19 containment policies and public information campaigns [53,54], which resulted in the improvement of complying with infection control and prevention measures by children (higher adherence to mask wearing and hand washing) [55][56][57][58] and reduced the transmission of bacterial and viral pathogens in many countries worldwide [59]. Our systematic review showed different results from previous case reports in which only a limited preliminary assessment of the potential size and scope of the available ISN cases among SARS-CoV-2-infected children was performed [4,17,19,25,28,30,41]. We were able to report the first pooled effect size of ISN prevalence in hospitalized pediatric COVID-19 patients because this review is more comprehensive and included a total of 34 studies [4][5][6][7], including a total of 64 COVID-19 children. The inclusion of 22 recently published studies [15,16,18,[20][21][22][23][24]26,[31][32][33][34][35][36][37][38][39][40][42][43][44] contributed to the refinement of the estimate of the pooled prevalence of ISN contributing to intestinal obstruction in COVID-19 pediatric patients. We estimated a comparable incidence of ISN among COVID-19 children (incidence: 40 to 70 cases per 100,000) to the previous studies that evaluated the yearly mean prevalence of ISN in children from Switzerland (incidence: 38 cases per 100,000) [60], Australia (incidence: 71 cases per 100,000) [61], the United Kingdom (incidence: 66 cases per 100,000) [62] and Singapore (incidence: 60 cases per 100,000) [63].
Analyzing the demographic and clinical characteristics of the ISN cases with COVID-19, we found that the age of presentation, preponderance in males, lack of previous medical history, location of affected intestinal segments, predominant ethnicity and symptoms from intestinal obstruction were maintained, like most reported cases of ISN. Our results align with some prior research that identified that ISN cases were more incident in the 1 to 12 month age group and in males [64,65], and most ISN episodes occurred in otherwise healthy and well-nourished children [66,67] and commonly involved the ileocecal junction (i.e., ileocolic type) [68,69]. We found that the development of COVID-19 in ISN children was highest in patients of White (Caucasian) and Hispanic ethnicity, and compared to whites, Hispanics had a two-fold lowered risk of ISN (39% and 20%, respectively). These findings are consistent with previous observations that estimated rates of ISN among Caucasian children are higher than among Hispanics and Asians [70,71]. Whether differences in factors such as genetics, diet or environment could explain this increased risk remains unclear. However, the differences in the frates of ISN by ethnicity could possibly be explained by low socioeconomic status [72], difference in access to health care or lack of accessibility to medical treatment [73], health care-seeking behavior [74] or lack of awareness among parents when their child presents with symptoms of ISN leading them to seek medical attention [75]. ISN classically presents in an infant or toddler with sudden onset of intermittent, severe and progressive abdominal pain, accompanied by inconsolable crying often with vomiting, palpable sausage-shaped abdominal mass, red currant jelly stools, anorexia, dehydration, irritability, abdominal tenderness, lethargy and pallor [76,77]. It is important to know that ISN can be an unusual manifestation of COVID-19. It is even more imperative to suspect ISN when a COVID-19 child presents with abdominal pain, vomiting, firm and palpable mass or blood in the stool [76,77]. In these cases, timely diagnosis is crucial for adequate treatment and a good prognosis [30]. A delay in diagnosis secondary to delayed presentation will lead to a delay in providing the adequate noninvasive treatment through enema reduction and an increased risk of treatment failure [78]. The COVID-19 pandemic has been reported to lead to the diagnostic delay of ISN and the deterioration of patients' clinical manifestations [79]; a high rate of bowel resection and morbidity was a consequence of delayed ISN presentation [80] and might have resulted in a lower number of ISN patients visiting the emergency department [81] or in some serious illnesses such as ISN remaining undiagnosed [82].
ISN may be the result of anatomical causes, associated diseases and, pertinent to cases included in this review, viral infections [83,84]. However, 75% of ISN cases occurred due to the lack of an identifiable lead point (i.e., idiopathic) [84]. One accepted theory regarding the pathogenesis of ISN and its correlation with viral infection is based on Peyer's patch swelling and lymph node hypertrophy acting as lead points. Adenovirus, rotavirus, norovirus, human herpes virus 6, astrovirus, enterovirus and cytomegalovirus, along with some parasites, have been identified as agents that can cause ISN [85,86]. SARS-CoV-2 has been known to infect cells via angiotensin-converting enzyme 2 (ACE-2) receptors and the transmembrane protease serine 2 (TMPRSS2) enzyme, which are highly expressed in the human's digestive system and mediate SARS-CoV-2 entry into the intestinal epithelial cells [87,88]. It is reasonable to hypothesize that any virus capable of triggering an enteric inflammatory response could produce an ISN in a vulnerable host, and inflammation of the small intestine and associated lymphatic hyperplasia from SARS-CoV-2 infection may result in ISN [36].
Depending on the duration of ISN illness and associated vomiting and blood loss, laboratory investigations for most of the ISN cases included in our review reflected dehydration, anemia, leukocytosis, or a combination of these [15,16,18,19,21,24,37,41,43]. However, laboratory abnormalities are not specific for ISN. Several imaging modalities can assist in the diagnosis of ISN [89]. The initial assessment should include plain abdominal radiographs to exclude perforation [90], which, if present, requires operative management rather than nonoperative reduction [91]; however, plain films have low sensitivity for the detection of ISN (<48%) [92]. Therefore, ultrasonography is the method of choice to detect ISN, and the sensitivity and specificity of this technique approaches 100% [93,94]. Ultrasound is better at characterizing pathological lead points than fluoroscopic techniques, can be used to monitor the success of a reduction procedure, and does not expose the patient to radiation [89]. A positive ultrasound shows evidence of a target sign (also called a doughnut sign or bull's eye sign), which represents layers of the intestine within the intestine and embodies ISN [94]. ISN can be recognized on computerized tomography, which may also identify the cause [95]; however, computerized tomography cannot be used to reduce the ISN [96], can be time consuming in children who may require sedation [97] and also exposes the patients to significant radiation [92].
Most of the ileocolic ISN patients who were hemodynamically stable and had no evidence of intestinal perforation were treated with nonoperative reduction techniques (i.e., pneumatic and/or hydrostatic). Pneumatic or hydrostatic pressure by enema is the treatment of choice to reduce ISN and has high success rates [98,99]. Surgical reduction may also be necessary if nonoperative reduction fails to reduce the ISN [100]. Consistent with recommendations from the American Pediatric Surgical Association [101], we found only a few children who received prophylactic antibiotics prior to or during nonoperative reduction, as there is no evidence that this practice is beneficial, likely because bacteremia and perforation are rare, except for in children with hemodynamic instability or critical illness [101]. Few of the ISN cases that had an ileo-ileal type were managed without nonoperative reduction, because the involvement of small bowel ISN is less likely to respond to pneumatic or hydrostatic reduction and more likely to reduce spontaneously (follow-up and bowel rest) [102].
We found that the mortality rate in ISN children infected with COVID-19 was significantly high in female patients with Asian ethnicity, in line with findings in previous reports that showed that females and children of Asian ethnicity with ISN were significantly associated with death [103,104] and in contradiction with data from a national study that examined trends in ISN-associated deaths among United States infant from 1979 to 2007, demonstrating that death was lower in females [105]. The difference in the mortality due to the fact of ISN based on gender has not been described in the literature previously; however, this might be attributed mainly to the differences in the severity of the ISN illness and/or inclusion criteria, or the level of health care infrastructure and general care-seeking practices in low-and middle-income countries [106,107]. Nevertheless, mortality in association with ISN is quite low in most parts of the world (<1%) [104]. Mortality in COVID-19 cases with ISN included in our review were complicated by multi-inflammatory systemic infection in children (i.e., cytokine storm), and the patients died due to the fact of subsequent multiple organ failure induced by the viral invasion [108].

Limitations of the Study
First, while all of the evidence discussed was based on one case-series, a few cohorts and many case reports, many of these were small and performed in single centers and are not necessarily generalizable to SARS-CoV-2-infected children with ISN. Second, to assess factors associated with mortality in ISN children infected with SARS-CoV-2, a larger cohort of patients is needed. Last, the study was not registered in Prospero, an international prospective register of systematic reviews, as this might have added extra work, and the merit was mostly limited to the avoidance of duplication.

Conclusions
Children with SARS-CoV-2 infection are at low risk to develop ISN and may experience SARS-CoV-2-induced ARDS or pneumonia and need ICU admission and mechanical ventilation. Female gender, Asian ethnicity, failure to ISN reduction treatment (pneumatic or surgical), admission to ICU, mechanical ventilation and suffering from ARDS were significantly associated with death following ISN in pediatric COVID-19 patients. These findings may help to design targeted interventions that raise health care providers' awareness regarding the risk of intestinal obstruction among infants who present to the emergency department.