Gastroenterology Research and Practice

Gastroenterology Research and Practice / 2017 / Article

Research Article | Open Access

Volume 2017 |Article ID 7182429 | 6 pages | https://doi.org/10.1155/2017/7182429

Ileostomy Prolapse in Children with Intestinal Dysmotility

Academic Editor: Greger Lindberg
Received10 May 2017
Accepted20 Jul 2017
Published18 Sep 2017

Abstract

Background. A relationship between intestinal motility and ileostomy prolapse has been suggested but not demonstrated objectively. Aims. This study evaluated the association between ileostomy prolapse and intestinal dysmotility in children. Methods. IRB-approved retrospective review of 163 patients with ileostomies (1998–2014) at a single institution. Patients were categorized as having clinical dysmotility as a primary diagnosis (), clinically suspected dysmotility based on underlying diagnosis (), or intestinal dysmotility unlikely () at the time of ileostomy present. Intestinal manometry was categorized as normal () or abnormal (). Primary outcome was pathologic stoma prolapse. Multivariate analysis using a logistic regression model and log-rank test to compare stoma prolapse rates over time between motility groups were used. Results. Clinical diagnosis of dysmotility () and manometric findings of dysmotility () were independently associated with stoma prolapse. Clinical dysmotility correlated with manometric findings (). Prolapse occurred in 42% of patients with dysmotility, 34% of patients with suspected dysmotility, and 24% of patients with normal motility. One-year prolapse-free stoma “survival” was 45% for dysmotility, 72% for suspected dysmotility, and 85% for intestinal dysmotility unlikely groups (). Conclusions. Children with intestinal dysmotility are at great risk for stoma prolapse. Intestinal manometry could help identify these patients preoperatively.

1. Introduction

Chronic intestinal pseudo-obstruction (CIPO), first described in 1978, is a syndrome characterized by severe congenital gastrointestinal dysmotility and frequent episodes mimicking mechanical obstruction. Despite medical and surgical therapy, the morbidity and mortality associated with intestinal motility remain high [1, 2]. When surgery is required, both proximal (gastrostomy or jejunostomy) and distal (ileostomy or colostomy) decompression are frequently attempted [1]; however, these are not curative procedures and have high rates of complication [2, 3].

Ileostomy creation has been associated with frequent morbidities in both adults and children, including skin excoriation, bleeding, obstruction, stenosis, fistula formation, prolapse, malnutrition, and reoperations [46]. Prolapse is reported in 13% of adult ileostomies, and in the setting of CIPO, intestinal reoperations have been associated with increased mortality [3, 6]. A relationship between intestinal motility and ileostomy prolapse has been suggested anecdotally, yet this link has not been demonstrated objectively [7]. The purpose of this study is to evaluate the incidence of ileostomy prolapse in children with and without intestinal dysmotility.

2. Methods

Following IRB approval (protocol #P0012914), all patients with ileostomies present (1998–2014) at a single institution were identified using a systematic search of the electronic medical record for related diagnosis and ICD-9 codes (560.89, 560.8, 560.9, 564.8, 564.89, 564.9, 569.6, 569.60, 569.62, and 569.69) and CPT codes (44312, 44314, 4415, and 44310). After an original 205 patients were identified, 163 were verified by record review to have had ileostomies placed. Clinical characteristics recorded for each patient included indication for ileostomy creation, age, and weight at initial surgery, intestinal manometry results, and technical surgical details.

The hypothesis of this study was that patients with clinical and/or manometric small intestinal dysmotility would have a higher rate of ileostomy prolapse than patients with normal motility. To allow for a robust analysis, dysmotility was assessed with the use of both diagnostic categories based on clinical evaluation and intestinal manometry studies (). Prior to data analysis, each patient was reviewed by a gastroenterologist specializing in motility disorders to determine the best diagnostic category (L.R.). Patients with a clinical diagnosis of dysmotility or CIPO were placed in the “primary dysmotility” category (). Patients with a separate primary diagnosis but documentation of suspected dysmotility and patients with a diagnosis which frequently predisposes them to dysmotility (NEC, gastroschisis, atresia, aganglionosis, and cystic fibrosis) were categorized as “suspected dysmotility” (). All remaining patients were categorized as “intestinal dysmotility unlikely” (inflammatory bowel disease, constipation, anorectal malformations, and abdominal neoplasm; ). Of note, patients with intractable constipation were included in the “intestinal dysmotility unlikely” category because they had no upper intestinal symptoms. All of these patients had their constipation symptoms resolved completely with placement of an ileostomy. This grouping scheme was validated by using Cohen’s kappa coefficient to evaluate agreement between dysmotility categorization and the “gold-standard” diagnostic modality, intestinal manometry. Manometry studies were performed at the discretion of a gastroenterology staff both prior to and after initial ileostomy creation following a standardized protocol that includes 3 phases: fasting motility recording for 3 hours followed by feeding challenge when tolerated (either oral or via enteral tube) and a medication challenge (IV erythromycin to stimulate antral contractions and subcutaneous octreotide to stimulate phase III of the migratory motor complex).

The primary outcome was any pathologic stoma prolapse, defined as a prolapse episode requiring a physician-performed intervention (manual reduction with or without anesthesia, stoma revision, or stoma takedown) to achieve resolution. Patients were tracked until pathologic prolapse was documented, the stoma was reversed for other indications, or the patient was lost to follow-up. Demographic and clinical characteristics were assessed using Mann–Whitney U tests for continuous variables and Fisher’s rank test for categorical variables. Multivariate analysis was performed by a logistic regression model for each possible predictor of prolapse. Variables with a value ≤ 0.20 on univariate analysis were included in the final model. Kaplan-Meier survival tables and curves were generated and factors compared using the log-rank (Mantel-Cox) test.

3. Results

Clinical characteristics of the 163 patients with ileostomies included in this study are described in Table 1. At the time of ileostomy creation, these patients had a median age of 42 months (IQR 1.3–162). Median follow-up duration was 8 months (IQR 3–24). Most patients (76%) had end ileostomies while 9% had double-barrel ileostomies, and 15% had loop ileostomies.


Descriptive and clinical variablesAll patients

Age at stoma creation (months)42 (1.2–163)
Gender, male66 (41%)
Weight at stoma creation (kg)14 (5–38)
WAZ score at stoma creation−1.0 (−2.6 to −0.1)
On PN at stoma creation64 (39%)
Surgical approach at stoma creation
 Laparoscopic42 (29%)
 Open104 (71%)
Type of stoma
 End ileostomy124 (76%)
 Double-barrel ileostomy15 (9%)
 Loop ileostomy24 (15%)
Surgical technique at stoma creation
 RLQ stoma placement115 (71%)
 Internal fascial pexy1 (0.6%)
 External fascial pexy88 (54%)
Dysmotility Category
 Intestinal motility as primary diagnosis33 (20%)
 Intestinal dysmotility suspected60 (37%)
 Intestinal dysmotility unlikely70 (43%)

Continuous variables are reported as median (IQR); frequencies are reported as n (%). WAZ: weight for age z-score; PN: parenteral nutrition; RLQ: right lower quadrant. Operative data missing for 28 patients.

The primary diagnosis requiring ileostomy creation for each patient is listed in Table 2. Of the total population, 33 patients had CIPO as a primary diagnosis and indication for ileostomy creation. 60 patients had dysmotility suspected based on either underlying diagnosis or clinical assessment. The remaining 70 patients had an anatomic or other indication for ileostomy creation unrelated to small bowel motility. 10 (43%) of 23 patients who underwent manometry testing were diagnosed as dysmotile. The dysmotility categories correlated well with manometric findings ().


Diagnosisn

Intestinal dysmotility as primary diagnosis
 Chronic intestinal pseudo-obstruction (CIPO)33
Intestinal dysmotility suspected
 Necrotizing enterocolitis30
 Hirschsprung’s disease19
 Cystic fibrosis5
 Enteric volvulus2
 Intestinal atresia2
 Gastroschisis1
 Meconium pseudocyst1
Intestinal dysmotility unlikely
 Inflammatory bowel disease36
 Constipation15
 Anorectal malformations7
 Abdominal neoplasm7
 Others5

Overall, 38 patients (24%) had a documented episode of ileostomy prolapse requiring physician reduction or surgical revision at a median of only 2 months (IQR 0.3–3.5) following ileostomy creation. Sixty-eight (42%) patients underwent stoma takedown or revision prior to any prolapse after a median of 7.1 months (IQR 3.1–13.8). Fifty-six (34%) patients either reached the end of the study period without any prolapse () or were lost to follow-up () after a median of 30.6 months (IQR 14.5–62.8).

Prolapse occurred in 42% of patients with primary dysmotility, 34% of patients with clinically suspected dysmotility, and 24% of patients with intestinal dysmotility unlikely (). Following multivariate analysis (Table 3), only dysmotility confirmed by intestinal manometry remained significant (). No technical surgical variables (e.g., stoma location, laparoscopic versus open surgery, and fascial pexy) were associated with prolapse in this cohort. Log-rank testing estimated that one-year prolapse-free stoma “survival” was 45% for primary dysmotility, 72% for clinically suspected dysmotility, and 85% for dysmotility unlikely (, Figure 1).


ProlapseNo prolapse value

Age at stoma creation (months)29 (5–82)55 (1–188)0.31
Gender, male15/38 (40%)51/125 (41%)0.88
Weight (kg) at stoma creation13 (6–20)16 (5–46)0.12
WAZ score at stoma creation−0.8 (−3.0 to −0.1)−1.1 (−2.7 to −0.1)0.45
Dysmotility by motility test (number of dysmotile/number tested)7/10 (70%)3/13 (23%)0.024
On PN at stoma creation15/38 (40%)49/125 (39%)0.98
Laparoscopic versus open stoma creation0.23
 Laparoscopic7/34 (23%)35/112 (28%)
 Open27/34 (79%)77/112 (62%)
Type of stoma0.4
 End ileostomy26/38 (68%)98/125 (78%)
 Double-barrel ileostomy4/38 (11%)11/125 (9%)
 Loop ileostomy8/38 (21%)16/125 (13%)
RLQ stoma placement26/38 (68%)89/125 (71%)0.74
Internal stoma pexy1/31 (3%)0/104 (0%)0.07
External fascia tacking21/31 (68%)67/104 (64%)0.73
Dysmotility Category<0.001
 Intestinal motility as primary diagnosis16/38 (42%)17/125 (14%)
 Intestinal dysmotility suspected13/38 (34%)47/125 (38%)
 Intestinal dysmotility unlikely9/38 (24%)61/125 (49%)

Continuous variables are reported as median (IQR); frequencies are reported as n (%). WAZ: weight for age z-score; PN: parenteral nutrition; RLQ: right lower quadrant. Operative data missing for 7 patients in prolapse cohort and 21 patients in no prolapse cohort. Mann–Whitney U tests were used for continuous variables and chi-square tests for categorical variables.

4. Discussion

In this investigation, 163 children with end ileostomies were followed for a median of 8.4 (IQR 3–24) months to evaluate incidence of stoma prolapse, which was observed in 38 (24%) of all patients. Each patient was categorized into three groups based on clinical intestinal dysmotility, and this classification was validated by comparison to intestinal manometry results.

Multivariate regression demonstrated that intestinal manometry results diagnostic of dysmotility were associated with higher rates of prolapse. Significant agreement () was observed between manometry results and motility categorization, validating this approach for comparison. Prolapse appears to be primarily an early complication of ileostomy creation, occurring at a median of two months (IQR 0.3–3.5) and with only three occurrences of pathologic prolapse occurring more than one year after ileostomy creation. Consequently, the median follow-up duration of patients without prolapse was significantly longer than the median time to prolapse (). To further assess the possible interaction of dysmotility and prolapse, Kaplan-Meier analysis was performed. One-year prolapse-free stoma “survival” was poorest in patients with a primary diagnosis of intestinal dysmotility ().

Chronic intestinal pseudo-obstruction is described as an amalgam of congenital syndromes characterized by severe intestinal dysmotility with frequent symptoms of obstruction [8, 9]. Diagnosis is difficult and must follow careful elimination of other underlying pathologies including mechanical obstruction and aganglionosis [9, 10]. CIPO is frequently accompanied by abnormal biopsy or intestinal manometry results [10, 11]. Distinct variations of neurogenic and myogenic CIPO are reported, though many patients have idiopathic disease [11, 12]. Some series of familial disease have also been reported [13].

Successful medical and surgical management of children with CIPO has proven difficult, and multiple investigators have reported high rates of morbidity and mortality. The reported mortality rate varies between 0% and 23% [2, 3, 12, 14, 15]. Surviving patients frequently require long-term parenteral nutrition [1, 2, 12, 15] or eventual intestinal transplantation [1, 2]. Management is focused on improving nutrition and managing obstructive symptoms [1, 2, 16]. Surgery is generally limited to bowel decompression in the form of gastrostomy/jejunostomy and ileostomy or colostomy placement [13, 16, 17].

Ileostomy complications have frustrated patients and surgeons for as long as ileostomies have been performed [4, 6]. The morbidity of ostomies is especially high in infants and children [5, 1820]. In particular, ileostomy prolapse has proven a frequent complication [7, 14, 21]. Many authors have suggested a variety of approaches to prevent or correct prolapse, including suture fixation of the bowel to the abdominal wall (stoma pexy), divided loop ileostomy, subcutaneous tunneling of bowel, Deflux® (hyaluronic acid/dextranomer, Salix Pharmaceuticals Inc., Raleigh, NC) injection, and stoma revision or takedown [2129]. As none of these interventions have consistently proven effective, the potential risks and benefits of these options need to be very carefully assessed for each patient. This study was unable to identify any surgical technique which successfully reduced the incidence of stoma prolapse. Certainly, the lack of standardization in operative technique may contribute to the lack of any findings. In addition, it is possible, due to the retrospective nature of this analysis, that true differences could not be detected.

While intestinal motility correlated well with the clinical groups created, not all patients underwent upper intestinal manometry. The utility of preoperative manometry in identifying children at high risk for prolapse may be beneficial. Prospective investigations are necessary to determine if employment of this test may result in avoidance of an otherwise planned ileostomy or in more informed preoperative counseling of patients and families.

There are limitations to this study. Our study was retrospective in nature, and we cannot control for specific variations between surgeons for technical approach to ileostomy creation. Certainly, a prospective study controlling for surgical technique may determine if specific surgical techniques help prevent prolapse. Only 23 patients had manometry studies, limiting the number of patients diagnosed via this method. Prolapse may have influenced clinicians’ decision making to diagnosis dysmotility for patients that were diagnosed postoperatively; in the future, preoperative manometry studies may help confirm dysmotility prior to stoma formation. Additionally, while this study did have a 25% loss to follow-up, this is not unexpected in a long-term retrospective analysis. Of note, the median observation period for patients lost to follow-up was 30.6 (IQR 14.0–63.4) months, which is longer than the median time to prolapse by an order of magnitude, suggesting that lack of follow-up in these patients is unlikely to have affected the outcome of the analysis.

These data corroborate findings by Irtan et al. who have suggested an association between CIPO and stoma prolapse in a small group of patients with ileostomies and colostomies [7]. Ileostomy prolapse appears to be a relatively frequent and early complication in patients with clinical and/or manometric dysmotility. Chronic intestinal pseudo-obstruction and other dysmotility syndromes result in the need for complex management, and patients undergoing ileostomy for decompression may see benefits which outweigh the potential morbidity of ileostomy prolapse. The knowledge that stoma prolapse is indeed seen with higher frequency in this patient population helps to inform surgical decision making and counseling and will hopefully result in more focused investigations such as evaluation of the increased use of manometry to predict ileostomy morbidity. Management by a multidisciplinary team (including pediatric surgery, gastroenterology, nutrition, social work, and transplant surgery) with experience in management of CIPO may be of benefit to limit high-risk procedures and aid future prospective investigation.

Abbreviations

CIPO:Chronic intestinal pseudo-obstruction.

Disclosure

An earlier version of this work was presented as abstract in the APSA 46th Annual Meeting in 2015.

Conflicts of Interest

There are no competing interests to declare.

Authors’ Contributions

Eric A. Sparks, Jeremy G. Fisher, Faraz A. Khan, Leonel Rodriguez, and Biren P. Modi designed the research study. Cristine S. Velazco, Eric A. Sparks, Leonel Rodriguez, and Biren P. Modi performed the research. Brenna S. Fullerton, Eric A. Sparks, Cristine S. Velazco, Jeremy G. Fisher, Faraz A. Khan, Amber M. Hall, Tom Jaksic, Leonel Rodriguez, and Biren P. Modi analyzed the data. Amber M. Hall, Eric A. Sparks, Cristine S. Velazco, Brenna S. Fullerton, Tom Jaksic, Leonel Rodriguez, and Biren P. Modi wrote the paper.

References

  1. D. L. Faulk, S. Anuras, and J. Christensen, “Chronic intestinal pseudoobstruction,” Gastroenterology, vol. 74, 5, Part 1, pp. 922–931, 1978. View at: Google Scholar
  2. A. Lauro, R. De Giorgio, and A. D. Pinna, “Advancement in the clinical management of intestinal pseudo-obstruction,” Expert Review of Gastroenterology & Hepatology, vol. 9, no. 2, pp. 197–208, 2015. View at: Publisher Site | Google Scholar
  3. O. Goulet, F. Sauvat, and D. Jan, “Surgery for pediatric patients with chronic intestinal pseudo-obstruction syndrome,” Journal of Pediatric Gastroenterology and Nutrition, vol. 41, Supplement 1, pp. S66–S68, 2005. View at: Publisher Site | Google Scholar
  4. M. P. Pakarinen, A. Kurvinen, A. I. Koivusalo et al., “Surgical treatment and outcomes of severe pediatric intestinal motility disorders requiring parenteral nutrition,” Journal of Pediatric Surgery, vol. 48, no. 2, pp. 333–338, 2013. View at: Publisher Site | Google Scholar
  5. C. Sabbagh, A. Amiot, L. Maggiori, O. Corcos, F. Joly, and Y. Panis, “Non-transplantation surgical approach for chronic intestinal pseudo-obstruction: analysis of 63 adult consecutive cases,” Neurogastroenterology and Motility, vol. 25, no. 10, pp. e680–e686, 2013. View at: Publisher Site | Google Scholar
  6. B. N. Brooke, “The management of an ileostomy, including its complications,” Lancet, vol. 2, no. 6725, pp. 102–104, 1952. View at: Google Scholar
  7. G. Steinau, K. M. Ruhl, H. Hörnchen, and V. Schumpelick, “Enterostomy complications in infancy and childhood,” Langenbeck's Archives of Surgery, vol. 386, no. 5, pp. 346–349, 2001. View at: Publisher Site | Google Scholar
  8. R. Warren and L. S. McKittrick, “Ileostomy for ulcerative colitis; technique, complications, and management,” Surgery, Gynecology & Obstetrics, vol. 93, no. 5, pp. 555–567, 1951. View at: Google Scholar
  9. S. Irtan, M. Bellaïche, C. Brasher, A. El Ghoneimi, J. P. Cézard, and A. Bonnard, “Stomal prolapse in children with chronic intestinal pseudoobstruction: a frequent complication?” Journal of Pediatric Surgery, vol. 45, no. 11, pp. 2234–2237, 2010. View at: Publisher Site | Google Scholar
  10. O. Goulet, A. Jobert-Giraud, J. L. Michel et al., “Chronic intestinal pseudo-obstruction syndrome in pediatric patients,” European Journal of Pediatric Surgery, vol. 9, no. 2, pp. 83–89, 1999. View at: Publisher Site | Google Scholar
  11. S. Cucchiara, V. Annese, R. Minella et al., “Antroduodenojejunal manometry in the diagnosis of chronic idiopathic intestinal pseudoobstruction in children,” Journal of Pediatric Gastroenterology and Nutrition, vol. 18, no. 3, pp. 294–305, 1994. View at: Publisher Site | Google Scholar
  12. C. Faure, O. Goulet, S. Ategbo et al., “Chronic intestinal pseudoobstruction syndrome: clinical analysis, outcome, and prognosis in 105 children. French-Speaking Group of Pediatric Gastroenterology,” Digestive Diseases and Sciences, vol. 44, no. 5, pp. 953–959, 1999. View at: Google Scholar
  13. A. Shaw, H. Shaffer, K. Teja, T. Kelly, E. Grogan, and C. Bruni, “A perspective for pediatric surgeons: chronic idiopathic intestinal pseudoobstruction,” Journal of Pediatric Surgery, vol. 14, no. 6, pp. 719–727, 1979. View at: Publisher Site | Google Scholar
  14. H.-Y. Kim, J.-H. Kim, S.-E. Jung, S.-C. Lee, K.-W. Park, and W.-K. Kim, “Surgical treatment and prognosis of chronic intestinal pseudo-obstruction in children,” Journal of Pediatric Surgery, vol. 40, no. 11, pp. 1753–1759, 2005. View at: Publisher Site | Google Scholar
  15. M. Muto, H. Matsufuji, T. Tomomasa et al., “Pediatric chronic intestinal pseudo-obstruction is a rare, serious, and intractable disease: a report of a nationwide survey in Japan,” Journal of Pediatric Surgery, vol. 49, no. 12, pp. 1799–1803, 2014. View at: Publisher Site | Google Scholar
  16. C. Di Lorenzo, S. N. Reddy, J. Villanueva-Meyer, I. Mena, S. Martin, and P. E. Hyman, “Cisapride in children with chronic intestinal pseudoobstruction. An acute, double-blind, crossover, placebo-controlled trial,” Gastroenterology, vol. 101, no. 6, pp. 1564–1570, 1991. View at: Google Scholar
  17. M. M. Murr, M. G. Sarr, and M. Camilleri, “The surgeon’s role in the treatment of chronic intestinal pseudoobstruction,” The American Journal of Gastroenterology, vol. 90, no. 12, pp. 2147–2151, 1995. View at: Google Scholar
  18. C. A. Musemeche, A. M. Kosloske, and R. R. Ricketts, “Enterostomy in necrotizing enterocolitis: an analysis of techniques and timing of closure,” Journal of Pediatric Surgery, vol. 22, no. 6, pp. 479–483, 1987. View at: Publisher Site | Google Scholar
  19. A. O’Connor and R. S. Sawin, “High morbidity of enterostomy and its closure in premature infants with necrotizing enterocolitis,” Archives of Surgery, vol. 133, no. 8, pp. 875–880, 1998. View at: Publisher Site | Google Scholar
  20. T. R. Weber, T. F. Tracy, M. L. Silen, and M. A. Powell, “Enterostomy and its closure in newborns,” Archives of Surgery, vol. 130, no. 5, pp. 534–537, 1995. View at: Publisher Site | Google Scholar
  21. K. Bielecki, “Recurrent ileostomy prolapse: is it a solved problem?” Techniques in Coloproctology, vol. 14, no. 3, pp. 283-284, 2010. View at: Publisher Site | Google Scholar
  22. K. Canil, P. Fitzgerald, G. Lau, G. Cameron, and M. Walton, “Button-pexy fixation for repair of ileostomy and colostomy prolapse,” Journal of Pediatric Surgery, vol. 30, no. 8, pp. 1148-1149, 1995. View at: Publisher Site | Google Scholar
  23. G. Crile and C. Y. Thomas, “Skin graft for prolapse of ileostomy,” Surgery, vol. 29, no. 3, pp. 473-474, 1951. View at: Google Scholar
  24. S. H. Ein, “Divided loop colostomy that does not prolapse,” American Journal of Surgery, vol. 147, no. 2, pp. 250–252, 1984. View at: Publisher Site | Google Scholar
  25. C. Festen, R. S. Severijnen, and F. H. vd Staak, “Enterostomy complications in infants,” Acta Chirurgica Scandinavica, vol. 154, no. 9, pp. 525–527, 1988. View at: Google Scholar
  26. I. L. Lichtenstein and S. S. Herzikoff, “Recurrent ileostomy prolapse, an old problem; presenting a new approach,” Annals of Surgery, vol. 141, no. 1, pp. 95–97, 1955. View at: Publisher Site | Google Scholar
  27. C. Mayo, “Button colopexy for prolapse of colon through colonic stoma,” Staff Meetings of the Mayo Clinic, vol. 14, pp. 439–441, 1939. View at: Google Scholar
  28. A. A. Pomeranz, “An operation for prevention of ileostomy prolapse,” Diseases of the Colon and Rectum, vol. 6, no. 5, pp. 381–384, 1963. View at: Publisher Site | Google Scholar
  29. N. Sohn, N. Schulman, M. A. Weinstein, and R. D. Robbins, “Ileostomy prolapse repair utilizing bidirectional myotomy and a meshed split-thickness skin graft,” American Journal of Surgery, vol. 145, no. 6, pp. 807-808, 1983. View at: Publisher Site | Google Scholar

Copyright © 2017 Eric A. Sparks et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

1256 Views | 265 Downloads | 1 Citation
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at help@hindawi.com to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19. Sign up here as a reviewer to help fast-track new submissions.