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Clinical outcome of cystic fibrosis presenting with or without meconium ileus: a matched cohort study
Journal of Pediatric Surgery (2006) 41, 1556 – 1560
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Clinical outcome of cystic fibrosis presenting with or without meconium ileus: a matched cohort study Anne Muncka,*, Miche`le Ge´rardina, Corinne Albertib, Catherine Ajzenmana, Muriel Lebourgeoisa, Yves Aigrainc, Jean Navarroa a
Cystic Fibrosis Centre, Hospital Robert Debre´ 48, bd Serurier, 75019 Paris, France Centre of Clinical Epidemiology, Hospital Robert Debre´ 48, bd Serurier, 75019 Paris, France c Department of Paediatric Surgery, Hospital Robert Debre´ 48, bd Serurier, 75019 Paris, France b
Index words: Cystic fibrosis; Meconium ileus; Nutritional status; Pulmonary function tests; Pseudomonas aeruginosa colonization; CFTR analysis
Abstract Objective: This matched case-control study compared the nutritional and the pulmonary long-term outcomes of cystic fibrosis (CF) patients presenting a history of meconium ileus (MI) with earlydiagnosed symptomatic CF without MI (non-MI). Material and Method: Twenty-six patients with CF treated for MI between 1980 and 1997 have been matched for sex, birth date, and earliest CF symptomatic diagnosis for the children with non-MI CF. Clinical characteristics, genotype and complications were evaluated as well as the progression of the CF disease from infancy to 15 years old by nutritional status (z score weight, z score height), pulmonary function tests (PFTs) (FVC and FEV1), and Pseudomonas aeruginosa acquisition. Results: Median duration of the follow-up was 12.5 years (range, 10-17 years). Genotype identification showed no significant difference. Further on, the rate of complications and the occurrence of chronic P aeruginosa colonization did not differ. At age of 15 years (n = 13), nutritional status and PFTs did not demonstrate any significant difference. Conclusion: These results suggest that adequate initial nutritional and medical management of MI allows further similar nutritional status and PFTs compared with other early-diagnosed symptomatic CF patients. In this study, MI did not represent an additional risk factor for the patient’s life. D 2006 Elsevier Inc. All rights reserved.
Meconium ileus (MI) occurs in 10% to 20% of the neonates with cystic fibrosis (CF); it is the earliest clinical manifestation of the disease. Before 1970, patients with MI had a high operative mortality rate (up to 70%), and the long-term survival was significantly lower, compared with non-MI CF patients [1-4]. The introduction of diatrizoate meglumine (Gastrografin) enema as a nonoper-
* Corresponding author. Tel.: +33 1 40 03 47 54; fax: +33 1 40 03 47 55. E-mail address: [email protected] (A. Munck). 0022-3468/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2006.05.014
ative form of treatment in uncomplicated cases of MI [5] and the improvement of surgical techniques, combined with better neonatal postoperative care in the remaining patients with complications (atresia, volvulus, perforation, failure of Gastrografin), allowed between 86% and 100% of survival [2,6,7]. The management of neonates with MI required a multidisciplinary approach with appropriate nutritional support and optimal pulmonary care. The present study evaluated the clinical characteristics, genotype, and complications and compared long-term nutritional and pulmonary
Clinical outcome of CF presenting with or without MI outcomes between MI and non-MI CF patients followed up in 1 CF center with the same standardized pulmonary management and scheduled consultations.
1. Patients and method 1.1. Patients Between 1980 and 1997, a total of 26 children were diagnosed as having CF with an initial symptom of MI. They have been matched according to their sex and birth date (we have chosen the youngest CF-diagnosed child when there were alternatives) with 26 non-MI CF children followed up in the same CF center. Cystic fibrosis was confirmed by 2 positive sweat tests of Gibson and Cooke [8] and/or 2 CFTR mutations. Regular hospital consultations— at least quarterly—included anthropometric parameters and sputum analysis; pulmonary function tests (PFTs) from 6 years of age and precipitating Pseudomonas aeruginosa antibodies were at least yearly evaluated. Analysis included CFTR genotyping, birth weight, the occurrence of complications (digestive complications, diabetes, and hepatic involvement), and data from longitudinal follow-up focused on the assessment of nutritional status, PFT, and P aeruginosa acquisition.
1557
2. Results A total of 26 MI CF patients (13 females, 13 males) born between 1980 and 1997 were identified. Among them, 8 neonates had been treated medically with a successful Gastrografin enema, and 18 had needed a surgical procedure. Of these 18, 12 surgically treated neonates had an intestinal resection (median, 20 cm (20-25)). A temporary ileostomy was performed for 10 patients for a median duration of 58 days (range, 43-64 days). Nutritional support had been necessary for all the 18 surgical patients, even for those without an intestinal resection either by a central line (n = 12) for a median duration of 97 days (range, 60125 days) or by enteral continuous feeding (n = 8) for a median duration of 129 days (range, 80-238 days) or a combination of both techniques. Medically treated MI patients did not require a nutritional support. Patients’ characteristics are shown in Table 1. There was no significant difference demonstrated in birth weight. The median age at CF diagnosis in the MI group was 1 month (range, 0-3 months); meanwhile, the median age in the nonMI was 3.5 months (range, 2-23 months) ( P = .003). CFTR genotype distribution did not differ significantly between groups, but we could notice a trend toward less DF508 mutation in the MI patients. Pancreatic status determined by the use of a 3-day fat absorption study [12] identified pancreatic insufficiency for
1.2. Methods 1.2.1. Nutritional assessment Growth measurements of weight and length were performed every 3 months. Age- and sex-specific z scores for weight and height were computed using normalized growth reference curves from the National Centre for Health [9]. 1.2.2. Pulmonary function tests Spirometry was performed using a water-sealed spirometer (PK, Chatham, United Kingdom). Predicted values were those of Zapletel et al [10]. 1.2.3. Chronic P aeruginosa colonization Chronic P aeruginosa colonization was defined as persistent presence of P aeruginosa (z106 CFU/mL) in sputum obtained for at least 6 months or less when combined with the presence of 2 or more precipitating antibodies against P aeruginosa [11].
1.3. Statistical analysis Qualitative variables were expressed as numbers (percentages) and quantitative variables as median (first-third quartile). Comparisons between the 2 matched cohorts used the Maentel-Haenszel v 2 test for qualitative variables and the Wilcoxon signed rank test for quantitative variables. All the tests were bilateral with a level set at .05. Data analysis was performed with SAS 8.12 (SAS Institute Inc, Cary, NC) for PC.
Table 1
Patient characteristics based on MI vs non-MI MI (n = 26)
non-MI (n = 26) P
No.
No.
%
Sex Male 13 50 Female 13 50 Median birth 2.9 (2.7-3.5) weight (kg) Median age at 1 (0-3) diagnosis (m) Genotype F508/F508 10 38 F502/other 10 38 Other/other 6 23 Pancreatic 26 100 insufficiency Digestive complications DIOS 6 23 Appendicular 3 11 mucocele Pancreatitis 0 0 Gastroesophageal 9 35 reflux Diabetes 2 8 Hepatic involvement 11 42 Chronic P aeruginosa 4 15 a b
Wilcoxon rank sum test. Maentel-Haenszel v 2 statistic.
%
13 50 13 50 3 (2.8-3.5) 3.5 (2-23)
NSa .0003a
13 8 5 23
50 31 19 88
NSb NSb NSb NSb
3 2
11 8
NSb NS
0 8
0 31
NS NS
2 5 7
8 19 27
NSb .07b NSb
1558
A. Munck et al.
Table 2
Nutritional follow-up in CF patients with MI vs non non-MI Z score weight (median [first-third quartile])
1 y (n = 26) 3 y (n = 26) 6 y (n = 26) 10 y (n = 23) 15 y (n = 13) a
MI Non-MI MI Non-MI MI Non-MI MI Non-MI MI Non-MI
0.60 0.46 0.25 0.43 0.42 0.00 0.35 0.36 0.65 0.26
( ( ( ( ( ( ( ( ( (
1.13 1.23 0.80 0.84 0.43 0.46 1.32 0.88 1.36 1.52
to to to to to to to to to to
0.36) 0.04) 0.26) 0.07) 1.29) 0.50) 0.56) 0.32) 0.53) 0.03)
Z score height (median [first-third quartile]) 0.12 0.24 0.15 0.08 0.15 0.43 0.43 0.02 0.73 0.18
( ( ( ( ( ( ( ( ( (
1.04 1.17 0.63 0.77 0.67 0.64 1.28 1.09 1.05 1.75
to to to to to to to to to to
P NSa
0.96) 0.63) 1.16) 0.94) 1.11) 1.33) 0.79) 0.94) 0.88) 0.00)
NSa NSa NSa NSa
Wilcoxon rank sum test.
all the MI patients and for 88% of the non-MI patients (nonsignificant [NS]). The median duration of the follow-up was 12.5 years (range, 10-17 years) for both groups. We looked at the usual specific CF complications such as digestive manifestations: distal obstruction intestinal syndrome (MI, 23%; non-MI, 11%), appendicular mucocele (MI, 11%; non-MI, 8%), pancreatitis (none in both groups), gastroeosophageal reflux (MI, 35%; non-MI, 31%), or diabetes (MI and non-MI, 8%). With regard to hepatic involvement, analysis of the results showed an echographic steatosis with elevated hepatic biologic parameters in up to 42% in the MI and 19% in the non-MI groups ( P = .07), leading to ursodesoxycholic acid therapy. In addition, we described 1 cholelithiasis and 1 cirrhosis in the MI group and none in the non-MI group. With regard to P aeruginosa acquisition, there was no significant difference between groups considering the median age of acquisition or the number of patients: 21 patients (81%) in MI group and 18 patients (69%) in the nonMI group. Chronic P aeruginosa appeared for 4 MI patients (15%) and 7 non-MI patients (27%); this difference was not statistically significant. Only 1 patient acquired Burkholderia vietnamensis, and he belonged to the MI group. In these 2 cohorts, nutritional status and PFTs were assessed regularly (Tables 2 and 3). The median z scores for weight and height did not differ significantly at 1, 3, 6, 10, and 15 years old. However, data for the cohorts are still incomplete for age of 15 years. There were no differences either in FVC or FEV1 between patients with or without MI up to the age of 15 years. Furthermore, results for growth indexes or PFTs were similar in the surgically managed MI patients and the non-MI patients.
3. Discussion In some recent articles, CF patients with MI still have a poorer outlook in terms of long-term outcome [13-16].The mortality rate in the first year of life has dramatically decreased for patients born after 1973 because of the use of diatrizoate meglumine (Gastrografin) enema and the improvement of surgical techniques combined with better
neonatal postoperative care. The combination of bowel rest and nutrient availability improves the healing of the anastomosis and prevents malnutrition for these babies. Our patients benefited from these improvements; nutritional support either by parenteral nutrition and/or enteral continuous feeding was initiated for all the surgical MI patients to provide adequate energy intake and normal growth indexes from infancy through the adolescent period. With regard to birth weight, we found no significant difference between MI and non-MI neonates. Meanwhile, 2 studies [17,18] describe a lower birth weight in the MI group, the authors suggesting a detrimental effect of in utero enteral nutrition. No difference was found in genotype distribution, but both groups are probably too small; we would have expected more DF508 among the pancreatic insufficient MI patients—as observed in the French Cystic Fibrosis Registry [19]—according to the genotype-phenotype correlations [18]. Mornet et al [20] showed different haplotypic variants for CF chromosomes, suggesting that MI might constitute a specific clinical and genetic entity; it has not been confirmed on allele frequencies studied by Kerem et al [18]. Lai et al [13], in a recent report, observed, as we did, less patients with DF508 mutations in his MI group, but he did not identify a specific genotypic entity for them. With regard to the occurrence of CF complications such as digestive manifestations or diabetes or liver disease, we found no differences among these 2 small cohorts. In the 1990s, studies [21] provided information about a higher risk Table 3 Pulmonary function test follow-up in CF patients with MI vs non-MI FVC (median FEV1 (median [first-third [first-third quartile]) quartile]) 6 y (n = 26)
MI 96 (93-116) Non-MI 99 (89-106) 10 y (n = 23) MI 90 (78-104) Non-MI 100 (87-107) 15 y (n = 13) MI 83 (75-93) Non-MI 80 (62-87) a
Wilcoxon rank sum test.
86 102 76 94 66 74
(78-106) (90-111) (69-98) (78-101) (56-92) (54-81)
P
NSa NSa NSa
Clinical outcome of CF presenting with or without MI of liver injury in MI patients, but it has been recently questionable [15,22]. Our study nutritional assessment from infancy to adolescent period showed similar z score values for weight and height between MI and non-MI patients without a significant deterioration with increasing age. These results are very encouraging, even if data are still incomplete for age of 15 years (n = 13). Similar data have been reported by Evans et al [15] and Kerem et al [18] for their patients born after 1973; in the latter study, MI patients had significantly lower birth weight, but both cohorts had identical weight and height percentiles at age of 13 years. DelPin et al [6] observed also similar long-term decreases in growth percentiles for MI and non-MI patients even for those managed surgically. Clinical course of patients presenting MI was similar to other CF patients—if deaths attributable to postoperative complications are discounted—for Coutts et al [23]. Hudson and Phelan [24] reported that pulmonary status of MI patients was not different from that in affected siblings who were diagnosed early. Like these authors, we suggest that the earlier age at diagnosis may be advantageous to CF with MI; it offers opportunities for early symptomatic treatment and pulmonary care. A recent prospective study by Lai et al [13] involving 32 MI and 50 non-MI earlydiagnosed through neonatal screening identified a significant stunting and wasting of weight and height across all ages between groups, especially for the surgically treated MI; the mean daily dietary intakes of energy was 130% of the recommended daily allowance (RDA) for the MI group (vs 110%), with a more prevalent abnormal essential fatty acid profile; the modalities of the nutritional support were not mentioned, and the pulmonary function has not been studied. In our study, patients with MI—whatever their initial treatment—had similar PFT as non-MI patients (Table 2) even at 15 years; the good nutritional status of both groups may contribute to these results; a correlation has been described between growth indexes and survival curves [24]. In the literature, there are very few long-term follow-up studies of the nutritional and the pulmonary parameters in MI, compared with other CF patients [25]. Kerem et al [18], with 40 MI and 420 non-MI patients studied at 13 years old, and Fuchs and Langer [26], with a matched case-control cohort of 35 patients (symptomatic non-MI CF patients), had similar conclusions to ours. Another recent study [15] on a matched case-control cohort of 39 patients (newborn screened non-MI CF patients) showed, in the MI group, a significant lower pulmonary function but similar nutritional parameters suggesting a more severe phenotype. Li et al [16] evaluated the longitudinal pulmonary status up to 12 years old on 32 MI and 50 newborn screened non-MI CF patients; both groups had similar prevalence of P aeruginosa and Staphylococcus aureus, but MI patients had a worse lung function. In the Patient Registry of the USA Cystic Fibrosis Foundation [27], when compared with patients in the screened neonatal group, those in the MI group had a significantly greater risk of shortened survival.
1559 We found that patients with MI acquired P aeruginosa as frequently as the non-MI group and that chronic colonization with P aeruginosa showed similar patterns in both groups. For Kerem et al [18], the earlier acquisition of P aeruginosa among the MI patients emphasizes the risk of early exposure [28] and the need for CF teams to be very cautious with segregation of patients according to bacterial colonization.
4. Conclusion In our study, MI did not represent a risk factor for the patients’ life, compared with other early-diagnosed CF patients; adequate nutritional support, especially in surgically treated MI, allowed similar nutritional status and PFTs even at 15 years old.
References [1] Mc Lantlin JF, Dickson AS, Swain AJ. Meconium ileus: immediate and long-term survival. Arch Dis Child 1972;47:207 - 10. [2] Rescorla FJ, Grosfeld JL, West KJ, et al. Changing pattern of treatment and survival in neonates with meconium ileus. Arch Surg 1989;142:837 - 40. [3] Donnison AB, Schwachman H, Gross RE. A review of 164 children with meconium ileus seen at the Children’s Hospital Medical Center, Boston. Pediatrics 1966;37:833 - 50. [4] Kalayoglu M, Sieber WK, Rodnan JB, et al. Meconium ileus: a critical review of treatment and eventual prognosis. J Pediatr Surg 1971;6:290 - 300. [5] Noblett HR. Treatment of uncomplicated meconium ileus by Gastrografin enema: a preliminary report. J Pediatr Surg 1969;4:190 - 7. [6] Del Pin CA, Czyrko C, Ziegler MM, et al. Management and survival of meconium ileus: a 30-year review. Ann Surg 1992;215:179 - 85. [7] Caniano DA, Beaver BL. Meconium ileus: a fifteen year experience with forty-two neonates. Surgery 1987;102:699 - 703. [8] Gibson LE, Cooke RE. A test for concentration of electrolytes in sweat in cystic fibrosius of the pancreas utilizing pilocarpine by iontophoresis. Pediatrics 1959;23:545 - 9. [9] Sempe M, Pedron G, Roy-Perroy MP. Auxologie: me´thodes et se´quences. Paris7 Theraplix; 1979. [10] Zapletal A, Samanek M, Paul T. Lung function in children and adolescents. Methods, reference, values. In: Zapletal A, editor. Progress in respiration research. Basel, Switzerland. 1987. p. 104 - 13. [11] Hoiby N. Pseudomonas aeruginosa in cystic fibrosis. Diagnostic and prognostic significance of Pseudomonas aeruginosa precipitins determined by means of crossed immunoelectrophoresis. A survey. Acta Pathol Microbiol Scand 1977;[C](Suppl 262):83 - 96. [12] Van de Kamer JH, Huinik HTB, Weyers HA. Rapid method for the determination of fat in feces. J Biol Chem 1949;177:347 - 55. [13] Lai HC, Kosorok MR, Laxova A, et al. Nutritional status of patients with cystic fibrosis with meconium ileus: a comparison with patients without meconium ileus and diagnosed early through neonatal screening. Pediatrics 2000;105:53 - 61. [14] Robinson MJ, Norman AP. Life tables for cystic fibrosis. Arch Dis Child 1975;50:962 - 7. [15] Evans AK, Fitzgerald DA, Mc Kay KO. The impact of meconium ileus on the clinical course of children with cystic fibrosis. Eur Respir J 2001;18:784 - 9. [16] Li Z, Huichuan JL, Kosorok MR, et al. Longitudinal pulmonary status of cystic fibrosis children with meconium ileus. Pediatr Pulmonol 2004;38:277 - 84.
1560 [17] Lai HC, Corey M, Fitzsimmons SC, et al. Comparison of growth in patients with cystic fibrosis between United States and Canada. Am J Clin Nutr 1999;69:531 - 8. [18] Kerem E, Corey M, Kerem B, et al. Clinical and genetic comparisons of patients with cystic fibrosis with and without meconium ileus. J Pediatr 1989;114:767 - 73. [19] Feingold J, Guilloud-Bataille M. Genetic comparisons of patients with cystic fibrosis with or without meconium ileus. Clinical Centers of the French CF Registry. Ann Genet 1999;42:147 - 50. [20] Mornet E, Simon-Bouy B, Seree JL, et al. Genetic differences between cystic fibrosis with and without meconium ileus. Lancet 1988;1:376 - 88. [21] Maurage C, Lenaerts C, Weber A, et al. Meconium ileus and its equivalent as a risk factor for development of cirrhosis: an autopsy study in CF. J Pediatr Gastroenterol Nutr 1989;9:17 - 20. [22] Lenaerts C, Lapierre C, Patriquin H, et al. Surveillance for cystic fibrosis-associated hepatobiliary disease by early ultrasound changes and predisposing factors. J Pediatr 2003;143:343 - 50.
A. Munck et al. [23] Coutts JAP, Dochterty JG, Carachi R, et al. Clinical course of patients with cystic fibrosis presenting meconium ileus. Br J Surg 1997;84:555. [24] Hudson I, Phelan PD. Are sex, age at diagnosis or mode of presentation prognostic factors for cystic fibrosis? Pediatr Pulmonol 1987;3:288 - 97. [25] Corey M, Mc Laughlin FJ, Williams M, et al. A comparison of survival growth and pulmonary function in patients with cystic fibrosis in Boston and Toronto. J Clin Epidemiol 1988; 41:583 - 91. [26] Fuchs JR, Langer JC. Long-term outcome after neonatal meconium obstruction. Pediatrics 1998;104:7. [27] Lai HJ, Cheng Y, Cho H, et al. Association between initial disease presentation, lung disease outcomes, and survival in patients with cystic fibrosis. Am J Epidemiol 2004;159:537 - 46. [28] Farrell PM, Li Z, Kosorok MR, et al. Bronchopulmonary disease in children with cystic fibrosis after early or delayed diagnosis. Am J Respir Crit Care Med 2003;168:1100 - 8.
www.elsevier.com/locate/jpedsurg
Clinical outcome of cystic fibrosis presenting with or without meconium ileus: a matched cohort study Anne Muncka,*, Miche`le Ge´rardina, Corinne Albertib, Catherine Ajzenmana, Muriel Lebourgeoisa, Yves Aigrainc, Jean Navarroa a
Cystic Fibrosis Centre, Hospital Robert Debre´ 48, bd Serurier, 75019 Paris, France Centre of Clinical Epidemiology, Hospital Robert Debre´ 48, bd Serurier, 75019 Paris, France c Department of Paediatric Surgery, Hospital Robert Debre´ 48, bd Serurier, 75019 Paris, France b
Index words: Cystic fibrosis; Meconium ileus; Nutritional status; Pulmonary function tests; Pseudomonas aeruginosa colonization; CFTR analysis
Abstract Objective: This matched case-control study compared the nutritional and the pulmonary long-term outcomes of cystic fibrosis (CF) patients presenting a history of meconium ileus (MI) with earlydiagnosed symptomatic CF without MI (non-MI). Material and Method: Twenty-six patients with CF treated for MI between 1980 and 1997 have been matched for sex, birth date, and earliest CF symptomatic diagnosis for the children with non-MI CF. Clinical characteristics, genotype and complications were evaluated as well as the progression of the CF disease from infancy to 15 years old by nutritional status (z score weight, z score height), pulmonary function tests (PFTs) (FVC and FEV1), and Pseudomonas aeruginosa acquisition. Results: Median duration of the follow-up was 12.5 years (range, 10-17 years). Genotype identification showed no significant difference. Further on, the rate of complications and the occurrence of chronic P aeruginosa colonization did not differ. At age of 15 years (n = 13), nutritional status and PFTs did not demonstrate any significant difference. Conclusion: These results suggest that adequate initial nutritional and medical management of MI allows further similar nutritional status and PFTs compared with other early-diagnosed symptomatic CF patients. In this study, MI did not represent an additional risk factor for the patient’s life. D 2006 Elsevier Inc. All rights reserved.
Meconium ileus (MI) occurs in 10% to 20% of the neonates with cystic fibrosis (CF); it is the earliest clinical manifestation of the disease. Before 1970, patients with MI had a high operative mortality rate (up to 70%), and the long-term survival was significantly lower, compared with non-MI CF patients [1-4]. The introduction of diatrizoate meglumine (Gastrografin) enema as a nonoper-
* Corresponding author. Tel.: +33 1 40 03 47 54; fax: +33 1 40 03 47 55. E-mail address: [email protected] (A. Munck). 0022-3468/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2006.05.014
ative form of treatment in uncomplicated cases of MI [5] and the improvement of surgical techniques, combined with better neonatal postoperative care in the remaining patients with complications (atresia, volvulus, perforation, failure of Gastrografin), allowed between 86% and 100% of survival [2,6,7]. The management of neonates with MI required a multidisciplinary approach with appropriate nutritional support and optimal pulmonary care. The present study evaluated the clinical characteristics, genotype, and complications and compared long-term nutritional and pulmonary
Clinical outcome of CF presenting with or without MI outcomes between MI and non-MI CF patients followed up in 1 CF center with the same standardized pulmonary management and scheduled consultations.
1. Patients and method 1.1. Patients Between 1980 and 1997, a total of 26 children were diagnosed as having CF with an initial symptom of MI. They have been matched according to their sex and birth date (we have chosen the youngest CF-diagnosed child when there were alternatives) with 26 non-MI CF children followed up in the same CF center. Cystic fibrosis was confirmed by 2 positive sweat tests of Gibson and Cooke [8] and/or 2 CFTR mutations. Regular hospital consultations— at least quarterly—included anthropometric parameters and sputum analysis; pulmonary function tests (PFTs) from 6 years of age and precipitating Pseudomonas aeruginosa antibodies were at least yearly evaluated. Analysis included CFTR genotyping, birth weight, the occurrence of complications (digestive complications, diabetes, and hepatic involvement), and data from longitudinal follow-up focused on the assessment of nutritional status, PFT, and P aeruginosa acquisition.
1557
2. Results A total of 26 MI CF patients (13 females, 13 males) born between 1980 and 1997 were identified. Among them, 8 neonates had been treated medically with a successful Gastrografin enema, and 18 had needed a surgical procedure. Of these 18, 12 surgically treated neonates had an intestinal resection (median, 20 cm (20-25)). A temporary ileostomy was performed for 10 patients for a median duration of 58 days (range, 43-64 days). Nutritional support had been necessary for all the 18 surgical patients, even for those without an intestinal resection either by a central line (n = 12) for a median duration of 97 days (range, 60125 days) or by enteral continuous feeding (n = 8) for a median duration of 129 days (range, 80-238 days) or a combination of both techniques. Medically treated MI patients did not require a nutritional support. Patients’ characteristics are shown in Table 1. There was no significant difference demonstrated in birth weight. The median age at CF diagnosis in the MI group was 1 month (range, 0-3 months); meanwhile, the median age in the nonMI was 3.5 months (range, 2-23 months) ( P = .003). CFTR genotype distribution did not differ significantly between groups, but we could notice a trend toward less DF508 mutation in the MI patients. Pancreatic status determined by the use of a 3-day fat absorption study [12] identified pancreatic insufficiency for
1.2. Methods 1.2.1. Nutritional assessment Growth measurements of weight and length were performed every 3 months. Age- and sex-specific z scores for weight and height were computed using normalized growth reference curves from the National Centre for Health [9]. 1.2.2. Pulmonary function tests Spirometry was performed using a water-sealed spirometer (PK, Chatham, United Kingdom). Predicted values were those of Zapletel et al [10]. 1.2.3. Chronic P aeruginosa colonization Chronic P aeruginosa colonization was defined as persistent presence of P aeruginosa (z106 CFU/mL) in sputum obtained for at least 6 months or less when combined with the presence of 2 or more precipitating antibodies against P aeruginosa [11].
1.3. Statistical analysis Qualitative variables were expressed as numbers (percentages) and quantitative variables as median (first-third quartile). Comparisons between the 2 matched cohorts used the Maentel-Haenszel v 2 test for qualitative variables and the Wilcoxon signed rank test for quantitative variables. All the tests were bilateral with a level set at .05. Data analysis was performed with SAS 8.12 (SAS Institute Inc, Cary, NC) for PC.
Table 1
Patient characteristics based on MI vs non-MI MI (n = 26)
non-MI (n = 26) P
No.
No.
%
Sex Male 13 50 Female 13 50 Median birth 2.9 (2.7-3.5) weight (kg) Median age at 1 (0-3) diagnosis (m) Genotype F508/F508 10 38 F502/other 10 38 Other/other 6 23 Pancreatic 26 100 insufficiency Digestive complications DIOS 6 23 Appendicular 3 11 mucocele Pancreatitis 0 0 Gastroesophageal 9 35 reflux Diabetes 2 8 Hepatic involvement 11 42 Chronic P aeruginosa 4 15 a b
Wilcoxon rank sum test. Maentel-Haenszel v 2 statistic.
%
13 50 13 50 3 (2.8-3.5) 3.5 (2-23)
NSa .0003a
13 8 5 23
50 31 19 88
NSb NSb NSb NSb
3 2
11 8
NSb NS
0 8
0 31
NS NS
2 5 7
8 19 27
NSb .07b NSb
1558
A. Munck et al.
Table 2
Nutritional follow-up in CF patients with MI vs non non-MI Z score weight (median [first-third quartile])
1 y (n = 26) 3 y (n = 26) 6 y (n = 26) 10 y (n = 23) 15 y (n = 13) a
MI Non-MI MI Non-MI MI Non-MI MI Non-MI MI Non-MI
0.60 0.46 0.25 0.43 0.42 0.00 0.35 0.36 0.65 0.26
( ( ( ( ( ( ( ( ( (
1.13 1.23 0.80 0.84 0.43 0.46 1.32 0.88 1.36 1.52
to to to to to to to to to to
0.36) 0.04) 0.26) 0.07) 1.29) 0.50) 0.56) 0.32) 0.53) 0.03)
Z score height (median [first-third quartile]) 0.12 0.24 0.15 0.08 0.15 0.43 0.43 0.02 0.73 0.18
( ( ( ( ( ( ( ( ( (
1.04 1.17 0.63 0.77 0.67 0.64 1.28 1.09 1.05 1.75
to to to to to to to to to to
P NSa
0.96) 0.63) 1.16) 0.94) 1.11) 1.33) 0.79) 0.94) 0.88) 0.00)
NSa NSa NSa NSa
Wilcoxon rank sum test.
all the MI patients and for 88% of the non-MI patients (nonsignificant [NS]). The median duration of the follow-up was 12.5 years (range, 10-17 years) for both groups. We looked at the usual specific CF complications such as digestive manifestations: distal obstruction intestinal syndrome (MI, 23%; non-MI, 11%), appendicular mucocele (MI, 11%; non-MI, 8%), pancreatitis (none in both groups), gastroeosophageal reflux (MI, 35%; non-MI, 31%), or diabetes (MI and non-MI, 8%). With regard to hepatic involvement, analysis of the results showed an echographic steatosis with elevated hepatic biologic parameters in up to 42% in the MI and 19% in the non-MI groups ( P = .07), leading to ursodesoxycholic acid therapy. In addition, we described 1 cholelithiasis and 1 cirrhosis in the MI group and none in the non-MI group. With regard to P aeruginosa acquisition, there was no significant difference between groups considering the median age of acquisition or the number of patients: 21 patients (81%) in MI group and 18 patients (69%) in the nonMI group. Chronic P aeruginosa appeared for 4 MI patients (15%) and 7 non-MI patients (27%); this difference was not statistically significant. Only 1 patient acquired Burkholderia vietnamensis, and he belonged to the MI group. In these 2 cohorts, nutritional status and PFTs were assessed regularly (Tables 2 and 3). The median z scores for weight and height did not differ significantly at 1, 3, 6, 10, and 15 years old. However, data for the cohorts are still incomplete for age of 15 years. There were no differences either in FVC or FEV1 between patients with or without MI up to the age of 15 years. Furthermore, results for growth indexes or PFTs were similar in the surgically managed MI patients and the non-MI patients.
3. Discussion In some recent articles, CF patients with MI still have a poorer outlook in terms of long-term outcome [13-16].The mortality rate in the first year of life has dramatically decreased for patients born after 1973 because of the use of diatrizoate meglumine (Gastrografin) enema and the improvement of surgical techniques combined with better
neonatal postoperative care. The combination of bowel rest and nutrient availability improves the healing of the anastomosis and prevents malnutrition for these babies. Our patients benefited from these improvements; nutritional support either by parenteral nutrition and/or enteral continuous feeding was initiated for all the surgical MI patients to provide adequate energy intake and normal growth indexes from infancy through the adolescent period. With regard to birth weight, we found no significant difference between MI and non-MI neonates. Meanwhile, 2 studies [17,18] describe a lower birth weight in the MI group, the authors suggesting a detrimental effect of in utero enteral nutrition. No difference was found in genotype distribution, but both groups are probably too small; we would have expected more DF508 among the pancreatic insufficient MI patients—as observed in the French Cystic Fibrosis Registry [19]—according to the genotype-phenotype correlations [18]. Mornet et al [20] showed different haplotypic variants for CF chromosomes, suggesting that MI might constitute a specific clinical and genetic entity; it has not been confirmed on allele frequencies studied by Kerem et al [18]. Lai et al [13], in a recent report, observed, as we did, less patients with DF508 mutations in his MI group, but he did not identify a specific genotypic entity for them. With regard to the occurrence of CF complications such as digestive manifestations or diabetes or liver disease, we found no differences among these 2 small cohorts. In the 1990s, studies [21] provided information about a higher risk Table 3 Pulmonary function test follow-up in CF patients with MI vs non-MI FVC (median FEV1 (median [first-third [first-third quartile]) quartile]) 6 y (n = 26)
MI 96 (93-116) Non-MI 99 (89-106) 10 y (n = 23) MI 90 (78-104) Non-MI 100 (87-107) 15 y (n = 13) MI 83 (75-93) Non-MI 80 (62-87) a
Wilcoxon rank sum test.
86 102 76 94 66 74
(78-106) (90-111) (69-98) (78-101) (56-92) (54-81)
P
NSa NSa NSa
Clinical outcome of CF presenting with or without MI of liver injury in MI patients, but it has been recently questionable [15,22]. Our study nutritional assessment from infancy to adolescent period showed similar z score values for weight and height between MI and non-MI patients without a significant deterioration with increasing age. These results are very encouraging, even if data are still incomplete for age of 15 years (n = 13). Similar data have been reported by Evans et al [15] and Kerem et al [18] for their patients born after 1973; in the latter study, MI patients had significantly lower birth weight, but both cohorts had identical weight and height percentiles at age of 13 years. DelPin et al [6] observed also similar long-term decreases in growth percentiles for MI and non-MI patients even for those managed surgically. Clinical course of patients presenting MI was similar to other CF patients—if deaths attributable to postoperative complications are discounted—for Coutts et al [23]. Hudson and Phelan [24] reported that pulmonary status of MI patients was not different from that in affected siblings who were diagnosed early. Like these authors, we suggest that the earlier age at diagnosis may be advantageous to CF with MI; it offers opportunities for early symptomatic treatment and pulmonary care. A recent prospective study by Lai et al [13] involving 32 MI and 50 non-MI earlydiagnosed through neonatal screening identified a significant stunting and wasting of weight and height across all ages between groups, especially for the surgically treated MI; the mean daily dietary intakes of energy was 130% of the recommended daily allowance (RDA) for the MI group (vs 110%), with a more prevalent abnormal essential fatty acid profile; the modalities of the nutritional support were not mentioned, and the pulmonary function has not been studied. In our study, patients with MI—whatever their initial treatment—had similar PFT as non-MI patients (Table 2) even at 15 years; the good nutritional status of both groups may contribute to these results; a correlation has been described between growth indexes and survival curves [24]. In the literature, there are very few long-term follow-up studies of the nutritional and the pulmonary parameters in MI, compared with other CF patients [25]. Kerem et al [18], with 40 MI and 420 non-MI patients studied at 13 years old, and Fuchs and Langer [26], with a matched case-control cohort of 35 patients (symptomatic non-MI CF patients), had similar conclusions to ours. Another recent study [15] on a matched case-control cohort of 39 patients (newborn screened non-MI CF patients) showed, in the MI group, a significant lower pulmonary function but similar nutritional parameters suggesting a more severe phenotype. Li et al [16] evaluated the longitudinal pulmonary status up to 12 years old on 32 MI and 50 newborn screened non-MI CF patients; both groups had similar prevalence of P aeruginosa and Staphylococcus aureus, but MI patients had a worse lung function. In the Patient Registry of the USA Cystic Fibrosis Foundation [27], when compared with patients in the screened neonatal group, those in the MI group had a significantly greater risk of shortened survival.
1559 We found that patients with MI acquired P aeruginosa as frequently as the non-MI group and that chronic colonization with P aeruginosa showed similar patterns in both groups. For Kerem et al [18], the earlier acquisition of P aeruginosa among the MI patients emphasizes the risk of early exposure [28] and the need for CF teams to be very cautious with segregation of patients according to bacterial colonization.
4. Conclusion In our study, MI did not represent a risk factor for the patients’ life, compared with other early-diagnosed CF patients; adequate nutritional support, especially in surgically treated MI, allowed similar nutritional status and PFTs even at 15 years old.
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