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analysis included only the three most frequent mutations in
ber of patients. In addition, like most previous studies, our
The limitations of the present study include the small num-
may be offerred to populations at high risk.
guinity rate in the population. In addition, genetic counseling
high among the population), and minimization of the consan-
dietary changes, reduction in the rate of smoking (which is very
KEY WORDS:
Preventive intervention that has been suggested includes
ties are very important and could have an important impact.
incidence and prevalence in the future. Also, educational activi-
tors had led us to expect a continuation of the increase in IBD
19 years [1]. The compensation of these aforementioned fac-
young society, with 60% of the population younger than age
The Bedouin Arab population in southern Israel is a very
of the NOD2/CARD15 mutation in this specific population.
nutrition. However, as we expected, we found a high prevalence
with a Western lifestyle, particularly with regard to hygiene and
change of lifestyle, including urbanization and modernization
Bedouin Arab is increasing [2], which may be attributed to the
We have reported before that the incidence of IBD among
clinical characteristics of the UC patients.
sis, no other differences were found regarding demographic or
P = 0.06) in the UC cohort. In our genotype-phenotype analy-
cally non-significant (46.7 ± 16.1 years vs. 30.7 ± 12.7 years;
higher among mutation carriers by about 15 years, but statisti-
In a genotype-phenotype analysis, age at diagnosis was
reported frequency in different ethnic groups [12-14].
is a relatively high-frequency rate compared with previously
the NOD2/CARD15 mutation in three patients (12%), which
The present study included 25 patients with UC. We found
including disease location and behavior.
In our study, no association was found in other parameters,
previously [6-9].
carrier group (P = 0.005). This finding has not been reported
mutation carriers were male, compared to 41% in the non-
tionship. Our results showed that 100% of the NOD2/CARD15
An important finding of the present work is the gender rela-
Similar findings were reported in previous studies [8,9,16,18].
131118-COHANIM - 131118-COHANIM | 4 - A | 18-11-13 | 11:24:13 | SR:-- | Cyan
riers compared to 28.82 ± 9.1 years in non-carriers (P = 0.04).
#131118-COHANIM - 131118-COHANIM | 4 - A | 18-11-13 | 11:24:13 | SR:-- | Black
131118-COHANIM - 131118-COHANIM | 4 - A | 18-11-13 | 11:24:13 | SR:-- | Yellow
ABSTRACT:
age on onset, with the age of 22.8 ± 4.5 years in mutation car-
131118-COHANIM - 131118-COHANIM | 4 - A | 18-11-13 | 11:24:13 | SR:-- | Magenta
relationship between the NOD2/CARD15 mutation and early
[5-10]. Our results, in agreement with other studies, showed a
genotype correlations of NOD2/CARD15 in CD patients
There is a large number of reports regarding phenotype-
genetic investigation in the future.
population could be an interesting population for further
nuclear families; each includes four patients with IBD. This
3,4
In the current IBD Bedouin Arab cohort, there are two
explain the high prevalence of genetic disease [4].
to have a high rate of consanguinity marriage, which might
and no more than 13%. The Bedouin Arab population is known
of Israel, which showed a lower frequency of mutation carriage
#
Original articles Original articles 3,4 and Micha J. Rapoport MD edication non-adherence may reduce the effectiveness 1 October 2013 and 31 March 2014 were retrieved from the Center with recommendation for BB insulin regimen between from the internal medicine wards of Assaf Harofeh Medical Demographic and clinical data of T2DM patients discharged DATA RETRIEVAl This research was a retrospective single center study. PATIENTS AND METHODS recommendation
earlier, known risk factors for such recurrences include previ- Correspondence 17. Fidder H, Olschwang S, Avidan B, et al. Association between mutations in the 22. Abreu MT, Taylor KD, Lin YC, et al. Mutations in NOD2 are associated with
ous anastomotic leak and congenital esophageal stenosis. No Dr. l. Bentur CARD15(NOD2) gene and Crohn’s disease in Israeli Jewish patients. Am J Med fibrostenosing disease in patients with Crohn’s disease. Gastroenterology 2002; 123:
Genet 2003; 121A: 240-4.
differences in short-term complication rates, anastomotic leak, Director, Dept. of Pediatric Pulmonology, Rappaport Children’s Hospital, 18. Zouiten-Mekki L, Zaouail H, Boubaker Jet al. CARD15/NOD2 in a Tunisian 679-88.
or anastomotic stricture were found between the thoracoscopic Rambam Health Care Campus, Haifa 3109601, Israel population with Crohn’s disease. Dig. Dis. Sci 2005; 50 (1): 130-5. 23. Bhullar M, Macrae F, Brown G, et al. Prediction of Crohn’s disease aggression
phone: (972-4) 777-4360, fax: (972-4) 777-4395
and open approaches [14]. email: l_bentur@rambam.health.gov.il 19. Hama I, Ratbi I, Reggoug S, et al. Non-association of Crohn’s disease with NOD2 through NOD2 /CARD15 gene sequencing in an Australian cohort. World J
Gastroenterol 2014; 20 (17): 5008-16.
In the current evaluation, the only factors associated with References gene variants in Moroccan patients. Gene 2012; 499: 121-3.
recurrent TEF were respiratory hospitalizations and diagnosis 1. Brosens E, Marsch F, de Jong EM, et al. Copy number variations in 375 patients 20. Boukercha A, Mesbah-Amroun H, Bouzidi A, et al. NOD2/CARD15 gene 24. Satsangi J, Silverberg MS, Vermeire S, et al. The Montreal classification of
inflammatory bowel disease: controversies, consensus, and implications. Gut 2006;
of viral bronchiolitis. Remarkably, we found more episodes of with oesophageal atresia and/or tracheoesophageal fistula. Eur J Hum Genet 2016; mutations in North Algerian patients with inflammatory bowel disease. World J 55: 749-53.
Gastroenterol 2015; 21 (25): 7786-94.
positive PCR for viruses per patient in the patients with recur- 24 (12): 1715-23. 21. Karban A, Atia O, Leitersdorf E, et al. The relation between NOD2/CARD15 25. Karban A, Waterman M, Panhuysen CI, et al. NOD2/CARD15 genotype and
rent TEF. PCR for viruses is not always sent for every patient 2. Brosens E, Ploeg M, van Bever Y, et al. Clinical and etiological heterogeneity in mutations and the prevalence and phenotypic heterogeneity of Crohn’s disease: phenotype differences between Ashkenazi and Sephardic Jews with Crohn`s
patients with tracheo-esophageal malformations and associated anomalies. Eur J
lessons from Israel Arab Crohn’s disease cohort. Dig Dis Sci 2005; 50 (9): 1692-7.
with clinical bronchiolitis. Moreover, the panel contains six Med Genet 2014; 57 (8): 440-52. disease. Am J Gastroenterol 20041134-40 :99 ;.
viruses, and it is possible that a patient had clinical bronchiolitis 3. Kovesi T, Rubin S. Long-term complications of congenital esophageal atresia and/ Capsule
caused by other viruses, such as rhinovirus and bocavirus. or tracheoesophageal fistula. Chest 2004; 126 (3): 915-25.
An association between de novo TEF and infectious agents 4. Nassar N, Leoncini E, Amar E, et al. Prevalence of esophageal atresia among 18
international birth defects surveillance programs. Birth Defects Res A Clin Mol
has been reported in immunosuppressed patients: in a renal Teratol 2012; 94 (11): 893-9. Interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice
transplant patient following Mycobacterium tuberculosis infec- 5. Acher CW, Ostlie DJ, Leys CM, Struckmeyer S, Parker M, Nichol PF. Long-term Despite decades of research, our understanding of the processes although IL-1β antibody treatment had no effect on lesion
tion [20], in a patient with human immunodeficiency virus-1 outcomes of patients with tracheoesophageal fistula/esophageal atresia: survey controlling late-stage atherosclerotic plaque stability remains size, it completely inhibited beneficial outward remodeling.
results from tracheoesophageal fistula/esophageal atresia online communities. Eur
who had necrotizing candidiasis of the trachea that resulted J Pediatr Surg 2016; 26 (6): 476-80. poor. A prevailing hypothesis is that reducing inflammation The authors also found that SMC-specific knockout of Il1r1
in the formation of a TEF [21], and in a patient with aplastic 6. Cartabuke RH, Lopez R, Thota PN. Long-term esophageal and respiratory may improve advanced plaque stability, as recently tested (encoding IL-1 receptor type 1) resulted in smaller lesions
outcomes in children with esophageal atresia and tracheoesophageal fistula.
anemia and invasive pulmonary aspergillosis [22]. The exact Gastroenterol Rep (Oxf) 2016; 4 (4): 310-14. in the Canakinumab Anti-inflammatory Thrombosis Outcome nearly devoid of SMCs and lacking a fibrous cap, whereas
mechanism for the development of these TEF complications is 7. Mirra V, Maglione M, Di Micco LL, Montella S, Santamaria F. Longitudinal follow- Study (CANTOS) trial, in which post-myocardial infarction macrophage-selective loss of IL-1R1 had no effect on lesion
unknown. The patients in our study who developed recurrence up of chronic pulmonary manifestations in esophageal atresia: a clinical algorithm subjects were treated with an IL-1β antibody. gomesz and size or composition. Taken together, these results showed
and review of the literature. Pediatr Neonatol 2015; 58 (1): 8-15.
of TEF were immunologically intact. We postulate that, fol- 8. Shah R, Varjavandi V, Krishnan U. Predictive factors for complications in children colleagues performed intervention studies in which smooth that IL-1β has multiple beneficial effects in late-stage murine
lowing TEF repair, the tracheoesophageal area might be more with esophageal atresia and tracheoesophageal fistula. Dis Esophagus 2015; 28 (3): muscle cell (SMC) lineage-tracing Apoe-/- mice with advanced atherosclerosis, including promotion of outward remodeling
vulnerable to additional insults, such as viral infections. 216-23. atherosclerosis were treated with anti-IL-1β or IgG control and formation and maintenance of an SMC- and collagen-rich
This study has several limitations. The main limitations are 9. Roberts K, Karpelowsky J, Fitzgerald DA, Soundappan SS V. Outcomes of antibodies. Surprisingly, they found that IL-1β antibody fibrous cap.
treatment between 18 and 26 weeks of Western diet feeding
oesophageal atresia and tracheo-oesophageal fistula repair. J Paediatr Child Health
the relatively small sample size and the retrospective nature. 2016; 52 (7): 694-8. induced a marked reduction in SMC and collagen content, but Nature Med 2018; 24: 1418
Not all patients underwent bronchoscopy prior to the first 10. Kassabian S, Baez-Socorro V, Sferra T, Garcia R. Eosinophilic esophagitis in increased macrophage numbers in the fibrous cap. Moreover, Eitan Israeli
surgery; hence, we could not clearly categorize the TEF. The patients with esophageal atresia and chronic dysphagia. World J Gastroenterol 2014;
20 (47): 18038-43.
study was based in a pediatric pulmonology institute at a ter- 11. Ghandour KE, Spitz L, Brereton RJ, Kiely EM. Recurrent tracheo-oesophageal
tiary center to which patients with more complicated health fistula: experience with 24 patients. J Paediatr Child Health 1990; 26 (2): 89-91. Capsule
issues are referred. Finally, as it is merely a descriptive study, 12. Benjamin B. Endoscopy in esophageal atresia and tracheoesophageal fistula. Ann
we were unable to establish the cause and effect relationships. Otol Rhinol Laryngol 1981; 90 (4 Pt 1): 376-82. Silicone breast implants and the risk of autoimmune/rheumatic disorders: a real-world analysis
It is impossible to determine whether the bronchiolitis itself 13. Sulkowski JP, Cooper JN, Lopez JJ, et al. Morbidity and mortality in patients with
esophageal atresia. Surgery 2014; 156 (2): 483-91.
increases the risk of recurrence of TEF, or whether patients who 14. Holcomb GW 3rd. Thoracoscopic surgery for esophageal atresia. Pediatr Surg Int watad and colleagues, in a cross-sectional study, used the 24,651 SBI recipients and 98,604 matched SBI-free controls.
develop recurrence of fistula are more vulnerable to common 2017; 33 (4): 475-81. computerized databases of Maccabi Healthcare Services (MHS), The adjusted OR between SBIs and being diagnosed with any
infectious agents in the process or have more hospitalizations 15. Fragoso AC, Tovar JA. The multifactorial origin of respiratory morbidity in patients which include up to 20 years of data on 2 million members. autoimmune/rheumatic disorders was 1.22 (95%CI 1.18–1.26).
with respiratory symptoms mimicking bronchiolitis. surviving neonatal repair of esophageal atresia. Front Pediatr 2014; 2: 39. Women with Silicone breast implants (SBIs) were identified by The strongest association with SBIs (OR > 1.5, P < 0.001) was
16. Bruch SW, Hirschl RB, Coran AG. The diagnosis and management of recurrent procedure and diagnosis codes, clinical breast examinations, recorded for Sjögren’s syndrome, systemic sclerosis (SSc), and
tracheoesophageal fistulas. J Pediatr Surg 2010; 45 (2): 337-40. and mammography referrals. Autoimmune/rheumatic disorders sarcoidosis (OR 1.58, 1.63, and 1.98, respectively). Similar
COnCluSIOnS 17. Smithers CJ, Hamilton TE, Manfredi MA, et al. Categorization and repair of were identified using the International Classification of results were calculated when analysis was limited to women
Even though cause and effect cannot be established, patients recurrent and acquired tracheoesophageal fistulae occurring after esophageal Diseases 9th revision (ICD-9) codes. Multivariable logistic with no breast cancer history. A multivariable Cox regression
atresia repair. J Pediatr Surg 2017; 52 (3): 424-30.
with a history of TEF and hospitalizations for viral bronchiolitis 18. Maizlin II, Chen JS, Smith NJ, Rogers DA. Closure of a traumatic esopha- regression models were used to calculate odds ratios (ORs) model yielded an HR of 1.45 (95%CI 1.21–1.73) for being
should be carefully evaluated for the possibility of recurrent gomediastinal fistula in a child by endoscopic fulguration and fibrin injection. Am and 95% confidence intervals (95%CIs). A Cox proportional diagnosed with at least one autoimmune/rheumatic disorder
TEF. In light of this data, we also suggest that vaccinations Surg 2016; 82 (9): 789-92. hazards model was used to calculate the hazard ratios (HRs) in women with SBI compared to those without.
against RSV and influenza for patients with a history of TEF 19. Battistella L, Marulli G, Comacchio GM, Mammana M, Di Gregorio G, Rea and 95%CIs among a subgroup of SBI recipients for whom Int J Epidemiol 2018 Oct 16. doi: 10.1093/ije/dyy217
F. Successful treatment of a recurrent wide tracheoesophageal fistula with a
may be beneficial. Further larger prospective studies should be bioabsorbable patch. Ann Thorac Surg 2016; 101 (5): e173-5. the year of SBIs insertion was available. The authors included Eitan Israeli
conducted to better understand the association between viral 20. Samhan M, Al-mousawi M, Halim M, Nampoory MRN. Tuberculous tracheo-
bronchiolitis and recurrent TEF. esophageal fistula in a renal transplant patient. Saudi J Kidney Dis Transplant 2005;
16 (2): 198-200.
21. Rusconi S, Meroni L, Galli M. Tracheoesophageal fistula in an HIV-1-positive man due “learning without thought is labor lost; thought without learning inspiration does not come
Acknowledgement to dual infection of Candida albicans and cytomegalovirus. Chest 1994; 106 (1): 284-5. like a bols perilous”
The authors acknowledge the statistical help of Ms. Ronit Leiba from 22. Yu Y, Zhu C, Qian X, Gao Y. Tracheoesophageal fistula induced by invasive
the Medical Statistics Unit, Rambam Health Care Campus. pulmonary aspergillosis. Ann Transl Med 2016; 4 (18): 345. Confucius, (551 BCE–479 BCE), Chinese philosopher
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