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Short research report
Congenital chylothorax: a prospective nationwide epidemiological study in Germany Anja Bialkowski,1 Christian F Poets,1 Axel R Franz,1,2 and the Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland Study Group3 1
Department of Neonatology, University Children’s Hospital of Tübingen, University of Tübingen, Tübingen, Germany 2 Center for Pediatric Clinical Studies, University Children’s Hospital of Tübingen, University of Tübingen, Tübingen, Germany 3 ESPED-Arbeitsgruppe, Koordinierungszentrum für Klinische Studien, Medizinische Fakultät der Heinrich-HeineUniversität Düsseldorf, Germany Correspondence to Dr Anja Bialkowski, Department of Neonatology, University Children’s Hospital of Tübingen, Calwerstr. 7, Tübingen 72076, Germany; [email protected] Received 30 July 2014 Revised 7 November 2014 Accepted 12 November 2014 Published Online First 5 December 2014
ABSTRACT Background Congenital chylothorax (CCT) is a rare disease of unknown aetiology. Treatment approaches vary; none has been evaluated prospectively. Objective To prospectively determine incidence, treatment and outcome of infants with CCT born in Germany in 2012. Design CCT was defined as non-traumatic chylous pleural effusion within 28 days after birth. As part of the Surveillance Unit for Rare Pediatric Conditions in Germany (Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland), all paediatric departments (n=432) received monthly reporting cards to notify the study centre of CCT cases, which were analysed based on anonymised questionnaires and discharge summaries. Data are shown as median (range) or n/N. Results Of 37 cases reported, 28 met inclusion criteria. Questionnaires and/or discharge summaries were available for 27/28. Assuming complete reporting, the incidence of CCT was 1:24 000. Nine infants suffered from proven or suspected syndromal anomalies, most frequently Noonan syndrome (5/9). Postnatally, 23 required mechanical ventilation, 3 continuous positive airway pressure; only 1 had no respiratory support. 17 infants were treated with inotropes/vasopressors, 25 required pleural drainage for 11 (1–36) days. In 13 infants, enteral feeds were withheld initially; 25 received medium-chain triglyceride diet at some time, 9 were treated with octreotide or somatostatin. 18 infants survived without, 6 with sequelae attributable to the underlying disorder; 3 infants died (median age at death 37 (2–144) days). Duration of hospital stay in survivors was 51 (20–127) days. Infants treated with octreotide or somatostatin had similar outcomes compared with those not treated. Conclusions Based on this small observational study, CCT seems to have a favourable prognosis if not associated with genetic disorders.
INTRODUCTION
To cite: Bialkowski A, Poets CF, Franz AR, et al. Arch Dis Child Fetal Neonatal Ed 2015;100: F169–F172.
Congenital chylothorax (CCT) is a rare and potentially life-threatening condition that may take a favourable course in the absence of complications and genetic anomalies. The diagnosis of chylothorax is usually made based on a pleural effusion characterised by a triglyceride level >1.1 mmol/L (with enteral fat intake) and a cell count >1000/mL with a lymphocyte fraction >80%.1–3 CCT is the most common type of pleural effusion during the neonatal period.4 The incidence of CCT is estimated to be 1:73005–1:10 000.6 To our knowledge, no population-based incidence data have yet been reported.
What is already known on this topic ▸ Congenital chylothorax (CCT) is a rare and potentially life-threatening condition that may take a favourable course in the absence of complications and genetic anomalies. ▸ Therapeutic interventions have never been prospectively evaluated and include total parenteral nutrition, medium-chain triglyceride diet and octreotide/somatostatin.
What this study adds ▸ For the first time, a population-based birth prevalence of CCT of 1:24 000 was reported, and mortality was as low as 11% mostly caused by comorbidities. ▸ Use of octreotide or somatostatin for CCT was associated with longer duration of pleural drainage, higher proportions of infants with blood culture-positive sepsis and antithrombin administration. ▸ Nevertheless, outcome was similar in infants treated with octreotide/somatostatin and those not receiving these peptide hormones.
The aetiology of CCT is often unclear. Associations with congenital heart disease, chromosomal disorders (eg, Down, Turner or Noonan syndrome7), prenatal infections, birth trauma, thrombosis of the superior vena cava or other malformations (eg, primary congenital pulmonary lymphangiectasis) have been reported.4 8–10 The male/ female ratio is said to be 2:1.9 Recently, Bellini et al11 reported physiological and pathophysiological dynamics of pleural effusion and chylothorax highlighting three basic mechanisms leading to pleural effusion: increased transpleural filtration pressure, impaired lymphatic drainage and increased permeability. Prospective studies of therapeutic interventions for CCT have not yet been published. Therefore, there are no standardised, generally accepted treatment guidelines. This study aimed at prospectively obtaining population-based epidemiologic data on CCT in Germany and to evaluate incidence, course and current treatments to inform the design of prospective interventional studies.
Bialkowski A, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F169–F172. doi:10.1136/archdischild-2014-307274
F169
Downloaded from http://fn.bmj.com/ on February 21, 2015 - Published by group.bmj.com
Short research report METHOD As part of the Surveillance Unit for Rare Pediatric Conditions in Germany (Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland (ESPED)), all paediatric departments (n=432) received monthly reporting cards to notify the study centre of neonates with CCT. In total, 5059 inquiries were sent, of which 4790 responses were received (94.7%).12 Reports on the mailing card prompted immediate mailing of an anonymised three-page purpose-made questionnaire asking for information on demographics and the prenatal and postnatal course and also requesting an anonymised discharge summary.
Inclusion criteria/definition of CCT For this study, CCT was defined as non-traumatic pleural effusion with ≥60% lymphocytes detected antenatally or within 28 days after birth.
Statistical analyses Data are reported as median and range. Between-group comparisons of the non-normally distributed data were done by Wilcoxon test, χ2 test and Fisher’s exact test as appropriate. To determine the birth prevalence of CCT, the number of births in Germany reported by the National Bureau of Statistics for 2012 (ie, 673 544 live births)13 was used.
RESULTS A total of 37 cases of CCT were reported, of which 28 met inclusion criteria. Of the nine excluded infants, two each had solely chylous ascites, were reported twice (after having been transferred to another hospital), had chylous effusion of traumatic origin, were reported erroneously (one initially reported patient did not exist, one was withdrawn without explanation) and one did not meet inclusion criteria (chylothorax detected beyond neonatal period). Questionnaires and/or discharge summaries were available for 27/28. Assuming complete reporting, the incidence of CCT in 2012 was 1:24 000. Gestational age at birth was 33.2 (24.7–39.1) weeks, birth weight was 2500 (740–3940) g. The majority of infants (24/27) was born preterm, that is, at 80%, in the remaining infant, it was 76%. 13/27 infants were initially not fed enterally at all; 25 received medium-chain triglyceride (MCT) diet (22/25 received a 100% MCT diet and 6/25 an 80% MCT/20% long-chain triglyceride (LCT) diet) at some time. In total, 16 (59%) infants received albumin replacement, 10 (37%) immunoglobulins, 16 (59%) blood transfusions, 4 (15%) platelet transfusions and 13 (48%) fresh frozen plasma. F170
Antithrombin replacement was given to five (19%) infants, in two of them associated with the occurrence of venous thrombosis (one patient catheter-associated both in the inferior caval vein and the left subclavian vein, the other in the sinus sagittalis superior). Further data are summarised in table 1. Eighteen infants survived without, six with sequelae attributable to their underlying disorder. Duration of hospital stay in survivors was 51 (20–127) days. Three infants died (median age at death 37 (2–144) days), all with significant comorbidities (myotonic dystrophy, extreme prematurity, coarctation). Nine infants were treated with octreotide and/or somatostatin for 21 (10–45) days, with this therapy being introduced on postnatal day 7 (4–17). 6/9 infants with peptide hormone treatment were fed a 100% MCT diet and 2/9 an 80% MCT/20% LCT diet. One of these nine solely received somatostatin, one was treated with octreotide and somatostatin. Two infants received 3–8 mg/kg/h octreotide intravenously divided into three daily doses, five as continuous infusion with a maximum dose of 7 (n=2), 8 (n=1) or 10 mg/kg/h (n=2), respectively. In two infants, side effects were reported: hyperglycaemia and bloody stools. For two infants (those receiving somatostatine), no information on dose or on potential adverse effects was reported. Infants treated with octreotide/somatostatin had similar mortality compared with those not receiving any of these drugs. The duration of pleural drainage was longer, and administration of antithrombin as well as blood culture-positive sepsis was more frequent with octreotide/somatostatin treatment (table 2). Infants receiving such treatment tended to have longer hospital stays, longer duration of respiratory support and higher pleural drainage output. Six infants had been cared for in our institution, a large tertiary referral centre; two receiving octreotide. Analysing these six versus all other infants born in Germany in 2012 revealed no significant differences (data not shown).
DISCUSSION The incidence of CCT has previously been estimated between 1:7300 and 1:10 000 live births.5 6 9 These estimates were not population based. In our study, the incidence of CCT was only 1:24 000. This difference between estimates is likely due to different study designs, but our investigation may also have been
Table 1 Treatment and outcome data of infants with congenital chylothorax Demographic variable
N
Prenatal diagnosis Prenatal intervention Absolute leucocyte count in pleural effusion (1/mL) Relative lymphocyte count in pleural effusion (%) Any postnatal iNO treatment Duration of iNO treatment (days) Any blood culture-positive sepsis Any antibiotic therapy Duration of antibiotic therapy (days) Discharged home on medium-chain triglyceride diet Any surgical intervention Any OK-432 administration into pleura
27 27 23 18 26 26 27 26 26 20 27 27
23 (85%) 12 (44%) 2900 (65–47 230) 93.5 (76–99) 5 (19%) 2 (2–7) 6 (22%) 26 (100%) 13,5 (0–44) 13 (65%) 0 (0%) 0 (0%)
Data are presented as median (range) or n (%). The number of infants (N) in whom data were provided is given for each item. iNO, inhaled nitric oxide.
Bialkowski A, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F169–F172. doi:10.1136/archdischild-2014-307274
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Short research report Table 2 Infants with congenital chylothorax treated with octreotide/somatostatine versus those not receiving peptide hormone treatment
Birth weight (g) Gestational age at birth (weeks) Mortality Underlying genetic anomaly Duration of mechanical ventilation (days) Duration of continuous positive airway pressure (days) Duration of any respiratory support (days) Duration of pleural drainage (days) Total drainage output (mL) Length of hospital stay (days) Clinical sepsis Blood culture-positive sepsis Substitution of antithrombin Discharged on medium-chain triglyceride diet
Octreotide/somatostatin
No peptide hormone
p Value
2440 (1820–3800) 33.4 (30.0–39.1) 0/9 2/9 13.5 (3–105) 8.5 (1–14) 19.5 (10–107) 16 (7–36) 1802 (50–10 200) 59 (28–127) 7/9 5/9 4/9 5/7
2522 (740–3940) 33.9 (24.7–37.4) 3/18 7/18 4 (0–37) 4 (0–29) 15 (0–38) 9 (0–29) 581 (0–4504) 43 (20–83) 7/18 1/18 1/18 8/12
0.29 0.53 0.19 0.38 0.20 0.93 0.19 0.03 0.13 0.33 0.056 0.003 0.014 0.83
Data are presented as median (range) or n/N.
susceptible to chance variability in incidence because of its relatively short observational period of 12 months. Furthermore, incomplete reporting for fear that each reported case will entail a questionnaire that has to be filled in may have resulted in a falsely low incidence. In contrast, regular audits of ESPED’s return rate for completed questionnaires consistently exceeded 93%.14 Haines et al have reported a similar return rate for their chylothorax survey in the UK.15 A male/female ratio of 2:1 reported in other studies9 16 concurs with our findings; the reason for this is unknown. To ensure complete reporting, paediatric departments were asked to report all non-traumatic pleural effusions with relative lymphocyte counts as low as 60% (rather than the 80% reported in the literature). However, 17/18 infants with report on relative lymphocyte counts had >80% lymphocytes in their pleural effusion and the lowest value reported was 76%, well in agreement with the literature. In previous case series, mortality was around 15–20%,9 17 whereas mortality in this cohort was 11% and largely explained by existing comorbidities. Decreased mortality may reflect more comprehensive prenatal and postnatal management in recent years. In our study, 26 of 27 cases were detected antenatally, of which 12 were treated in utero by pleural puncture or pleural drainage, but the safety and efficacy of prenatal interventions yet needs to be elucidated. Postnatal treatment was, on the one hand, supportive, that is, included treatment of respiratory distress (by mechanical ventilation and drainage of the pleural effusion), complications (hypotension; systemic infection) and substitution of pleural losses (with albumin, immunoglobulins or antithrombin). On the other hand, reduction in chylous production was attempted either by withholding enteral nutrition and providing total parenteral nutrition, or by feeding an MCT diet.2 18 19 In the past, beneficial effects of octreotide or somatostatine on chylous fluid production have been claimed in several case series.20–22 Our data suggest that patients treated with these drugs were more seriously ill (see table 2), with significantly longer duration of pleural drainage and more infants with blood culture-positive sepsis or antithrombin administration. However, efficacy of this treatment needs to be evaluated in a prospective interventional trial. Safety of peptide hormone treatment has never been prospectively evaluated in newborns with CCT. So far, necrotising enterocolitis (NEC),23 transient hypothyroidism,6 transient
increases in liver enzymes24 and hyperglycaemia have been reported in CCT infants treated with these peptide hormones. Isolated, that is, non-NEC-associated bloody stools may need to be added to the list of potential side effects because these had been reported once, several days after discontinuation of peptide hormone treatment, with spontaneous resolution. Published dosing regimens for octreotide and somatostatine are quite variable.17 22 As expected, this is also evident in our data, reflecting insufficient knowledge on peptide hormone pharmacokinetics in infants with CCT. Based on this prospective epidemiological study, the clinical management approach in Germany seems to be quite heterogeneous. Several years prior to this study, we established a standardised treatment algorithm at our institution, quite similar to the one recently reported by Downie et al16 for CCT or by Panthongviriyakul and Bines25 for postoperative chylothorax. But to date, no standardised approach has been evaluated prospectively and there is yet no evidence that this standardised approach results in improved outcome. Again, the observational design and the small sample size of our study prohibit any firm conclusions. In summary, we report prospective population-based epidemiological, treatment and outcome data on CCT. The incidence of CCT found here was smaller than expected—and although outcome is mostly favourable, it is unclear to what extent treatment modalities actually improve outcome. We agree with Bellini et al17 that there is an evident need for an international multicentre trial including long-term follow-up. Contributors AB performed the study. She collected all clinical data and analysed it with the support of ARF and wrote the first draft of the manuscript. ARF contributed to the manuscript and performed the statistical analyses. CFP contributed to the manuscript and helped to design the study. AB and ARF designed the study and wrote the ethics submission. Competing interests None. Ethics approval Ethical Board of University of Tuebingen, Germany. Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES 1 2 3
Staats BA, Ellefson RD, Budahn LL, et al. The lipoprotein profile of chylous and non chylous pleural effusions. Mayo Clin Proc 1980;55:700–4. Straaten van HL, Gerards LJ, Krediet TG. Chylothorax in the neonatal period. Eur J Pediatr 1993;152:2–5. Büttiker V, Fanconi S, Birger R. Chylothorax in children: guidelines for diagnosis and management. Chest 1999;116:682–7.
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7 8 9 10
11
12 13
14
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Chernick V, Reed MH. Pneumothorax and chylothorax in the neonatal period. J Pediatr 1970;76:624–32. Ergaz Z, Bar-Oz B, Yatsiv I, et al. Congenital chylothorax: clinical course and prognostic significance. Pediatr Pulmonol 2009;44:806–11. Maayan-Metzger A, Sack J, Mazkereth R, et al. Somatostatin treatment of congenital chylothorax may induce transient hypothyroidism in newborns. Acta Paediatr 2005;94:785–9. Goens MB, Campbell D, Wiggins JW. Spontaneous chylothorax in Noonan syndrome. Am J Dis Child 1992;146:1453–6. Paget-Brwon A, Kattwinkel J, Rodgers BM, et al. The use of octreotide to treat congenital chylothorax. J Pediatr Surg 2006;41:845–7. Rocha G, Fernandez P, Rocha P, et al. Pleural effusions in the neonate. Acta Paediatr 2006;95:791–8. Moerman P, Vandenberghe K, Devlieger H, et al. Congenital pulmonary lymphangiectasis with chylothorax: a heterogeneous lympathic vessel abnormality. Am J Med Genet 1993;47:54–8. Bellini C, Ergaz Z, Boccardo F, et al. Dynamics of pleural effusion and chylothorax in the fetus and newborn: role of the lymphatic system. Lymphology 2013;46:75–84. ESPED Bericht [ESPED report] Monatszeitschrift Kinderheilkunde 10, Oct 2013, p964. Statistisches Bundesamt, Geburtentrends und Familiensituation in Deutschland. 2012. (Statistical department and family situation in Germany 2012) https://www. destatis.de/DE/Publikationen/Thematisch/Bevoelkerung/HaushalteMikrozensus/ Geburtentrends5122203129004.pdf?__blob=publicationFile (accessed 3 Jul 2014). Gobel U, Heinrich B, Krauth KA, et al. Process and outcome quality of the German Paediatric Surveillance Unit (ESPED). Klin Padiatr 2010;9:92–7.
15 16 17
18 19
20
21 22 23
24
25
Haines C, Walsh B, Fletcher M, et al. Chylothorax development in infants and children in the UK. Arch Dis Child 2014;99:724–30. Downie L, Sasi A, Malhotra A. Congenital chylothorax: associations and neonatal outcomes. J Paediatr Child Health 2014;50:234–8. Bellini C, Ergaz Z, Radicioni M, et al. Congenital fetal and neonatal visceral chylous effusions: neonatal chylothorax and chylous ascites revisited. A multicenter retrospective study. Lymphology 2012;45:91–102. Beghetti M, La Scala G, Belli D, et al. Etiology and management of pediatric chylothorax. J Pediatr 2000;136:653–8. Fernandez Alvarez JR, Djaffar Kalache K, Gruel EL. Management of spontaneous congenital chylothorax: oral medium-chain triglycerides versus total parenteral nutrition. Am J Perinatal 1999;16:415–20. Roehr CC, Jung A, Proquitte H, et al. Somatostatin or octreotide as treatment options for chylothorax in young children: a systematic review. Intensive Care Med 2006;32:650–7. Das A, Shah PS. Octreotide for the treatment of chylothorax in neonates. Cochrane Database Syst Rev 2007;(9):CD006388. Helin RD, Angeles STV, Bhat R. Octreotide therapy for chylothorax in infants and children: a brief review. Pediatr Crit Care Med 2006;7:576–9. Mohseni-Bod H, Macrae D, Slavik Z. Somatostatin analog (octreotide) in management of neonatal postoperative chylothorax: is it safe? Pediatr Crit Care Med 2004;5:356–7. Demirbilek H, Shah P, Arya VB, et al. Long-term follow-up of children with Congenital Hyperinsulinism on Octreotide Therapy. J Clin Endocrinol Metab 2014;99:3660–7. Panthongviriyakul C, Bines JE. Post-operative chylothorax in children: an evidence-based management algorithm. J Paediatr Child Health 2008;44:716–21.
Bialkowski A, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F169–F172. doi:10.1136/archdischild-2014-307274
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Congenital chylothorax: a prospective nationwide epidemiological study in Germany Anja Bialkowski, Christian F Poets, Axel R Franz and and the Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland Study Group Arch Dis Child Fetal Neonatal Ed 2015 100: F169-F172 originally published online December 5, 2014
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Short research report
Congenital chylothorax: a prospective nationwide epidemiological study in Germany Anja Bialkowski,1 Christian F Poets,1 Axel R Franz,1,2 and the Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland Study Group3 1
Department of Neonatology, University Children’s Hospital of Tübingen, University of Tübingen, Tübingen, Germany 2 Center for Pediatric Clinical Studies, University Children’s Hospital of Tübingen, University of Tübingen, Tübingen, Germany 3 ESPED-Arbeitsgruppe, Koordinierungszentrum für Klinische Studien, Medizinische Fakultät der Heinrich-HeineUniversität Düsseldorf, Germany Correspondence to Dr Anja Bialkowski, Department of Neonatology, University Children’s Hospital of Tübingen, Calwerstr. 7, Tübingen 72076, Germany; [email protected] Received 30 July 2014 Revised 7 November 2014 Accepted 12 November 2014 Published Online First 5 December 2014
ABSTRACT Background Congenital chylothorax (CCT) is a rare disease of unknown aetiology. Treatment approaches vary; none has been evaluated prospectively. Objective To prospectively determine incidence, treatment and outcome of infants with CCT born in Germany in 2012. Design CCT was defined as non-traumatic chylous pleural effusion within 28 days after birth. As part of the Surveillance Unit for Rare Pediatric Conditions in Germany (Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland), all paediatric departments (n=432) received monthly reporting cards to notify the study centre of CCT cases, which were analysed based on anonymised questionnaires and discharge summaries. Data are shown as median (range) or n/N. Results Of 37 cases reported, 28 met inclusion criteria. Questionnaires and/or discharge summaries were available for 27/28. Assuming complete reporting, the incidence of CCT was 1:24 000. Nine infants suffered from proven or suspected syndromal anomalies, most frequently Noonan syndrome (5/9). Postnatally, 23 required mechanical ventilation, 3 continuous positive airway pressure; only 1 had no respiratory support. 17 infants were treated with inotropes/vasopressors, 25 required pleural drainage for 11 (1–36) days. In 13 infants, enteral feeds were withheld initially; 25 received medium-chain triglyceride diet at some time, 9 were treated with octreotide or somatostatin. 18 infants survived without, 6 with sequelae attributable to the underlying disorder; 3 infants died (median age at death 37 (2–144) days). Duration of hospital stay in survivors was 51 (20–127) days. Infants treated with octreotide or somatostatin had similar outcomes compared with those not treated. Conclusions Based on this small observational study, CCT seems to have a favourable prognosis if not associated with genetic disorders.
INTRODUCTION
To cite: Bialkowski A, Poets CF, Franz AR, et al. Arch Dis Child Fetal Neonatal Ed 2015;100: F169–F172.
Congenital chylothorax (CCT) is a rare and potentially life-threatening condition that may take a favourable course in the absence of complications and genetic anomalies. The diagnosis of chylothorax is usually made based on a pleural effusion characterised by a triglyceride level >1.1 mmol/L (with enteral fat intake) and a cell count >1000/mL with a lymphocyte fraction >80%.1–3 CCT is the most common type of pleural effusion during the neonatal period.4 The incidence of CCT is estimated to be 1:73005–1:10 000.6 To our knowledge, no population-based incidence data have yet been reported.
What is already known on this topic ▸ Congenital chylothorax (CCT) is a rare and potentially life-threatening condition that may take a favourable course in the absence of complications and genetic anomalies. ▸ Therapeutic interventions have never been prospectively evaluated and include total parenteral nutrition, medium-chain triglyceride diet and octreotide/somatostatin.
What this study adds ▸ For the first time, a population-based birth prevalence of CCT of 1:24 000 was reported, and mortality was as low as 11% mostly caused by comorbidities. ▸ Use of octreotide or somatostatin for CCT was associated with longer duration of pleural drainage, higher proportions of infants with blood culture-positive sepsis and antithrombin administration. ▸ Nevertheless, outcome was similar in infants treated with octreotide/somatostatin and those not receiving these peptide hormones.
The aetiology of CCT is often unclear. Associations with congenital heart disease, chromosomal disorders (eg, Down, Turner or Noonan syndrome7), prenatal infections, birth trauma, thrombosis of the superior vena cava or other malformations (eg, primary congenital pulmonary lymphangiectasis) have been reported.4 8–10 The male/ female ratio is said to be 2:1.9 Recently, Bellini et al11 reported physiological and pathophysiological dynamics of pleural effusion and chylothorax highlighting three basic mechanisms leading to pleural effusion: increased transpleural filtration pressure, impaired lymphatic drainage and increased permeability. Prospective studies of therapeutic interventions for CCT have not yet been published. Therefore, there are no standardised, generally accepted treatment guidelines. This study aimed at prospectively obtaining population-based epidemiologic data on CCT in Germany and to evaluate incidence, course and current treatments to inform the design of prospective interventional studies.
Bialkowski A, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F169–F172. doi:10.1136/archdischild-2014-307274
F169
Downloaded from http://fn.bmj.com/ on February 21, 2015 - Published by group.bmj.com
Short research report METHOD As part of the Surveillance Unit for Rare Pediatric Conditions in Germany (Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland (ESPED)), all paediatric departments (n=432) received monthly reporting cards to notify the study centre of neonates with CCT. In total, 5059 inquiries were sent, of which 4790 responses were received (94.7%).12 Reports on the mailing card prompted immediate mailing of an anonymised three-page purpose-made questionnaire asking for information on demographics and the prenatal and postnatal course and also requesting an anonymised discharge summary.
Inclusion criteria/definition of CCT For this study, CCT was defined as non-traumatic pleural effusion with ≥60% lymphocytes detected antenatally or within 28 days after birth.
Statistical analyses Data are reported as median and range. Between-group comparisons of the non-normally distributed data were done by Wilcoxon test, χ2 test and Fisher’s exact test as appropriate. To determine the birth prevalence of CCT, the number of births in Germany reported by the National Bureau of Statistics for 2012 (ie, 673 544 live births)13 was used.
RESULTS A total of 37 cases of CCT were reported, of which 28 met inclusion criteria. Of the nine excluded infants, two each had solely chylous ascites, were reported twice (after having been transferred to another hospital), had chylous effusion of traumatic origin, were reported erroneously (one initially reported patient did not exist, one was withdrawn without explanation) and one did not meet inclusion criteria (chylothorax detected beyond neonatal period). Questionnaires and/or discharge summaries were available for 27/28. Assuming complete reporting, the incidence of CCT in 2012 was 1:24 000. Gestational age at birth was 33.2 (24.7–39.1) weeks, birth weight was 2500 (740–3940) g. The majority of infants (24/27) was born preterm, that is, at 80%, in the remaining infant, it was 76%. 13/27 infants were initially not fed enterally at all; 25 received medium-chain triglyceride (MCT) diet (22/25 received a 100% MCT diet and 6/25 an 80% MCT/20% long-chain triglyceride (LCT) diet) at some time. In total, 16 (59%) infants received albumin replacement, 10 (37%) immunoglobulins, 16 (59%) blood transfusions, 4 (15%) platelet transfusions and 13 (48%) fresh frozen plasma. F170
Antithrombin replacement was given to five (19%) infants, in two of them associated with the occurrence of venous thrombosis (one patient catheter-associated both in the inferior caval vein and the left subclavian vein, the other in the sinus sagittalis superior). Further data are summarised in table 1. Eighteen infants survived without, six with sequelae attributable to their underlying disorder. Duration of hospital stay in survivors was 51 (20–127) days. Three infants died (median age at death 37 (2–144) days), all with significant comorbidities (myotonic dystrophy, extreme prematurity, coarctation). Nine infants were treated with octreotide and/or somatostatin for 21 (10–45) days, with this therapy being introduced on postnatal day 7 (4–17). 6/9 infants with peptide hormone treatment were fed a 100% MCT diet and 2/9 an 80% MCT/20% LCT diet. One of these nine solely received somatostatin, one was treated with octreotide and somatostatin. Two infants received 3–8 mg/kg/h octreotide intravenously divided into three daily doses, five as continuous infusion with a maximum dose of 7 (n=2), 8 (n=1) or 10 mg/kg/h (n=2), respectively. In two infants, side effects were reported: hyperglycaemia and bloody stools. For two infants (those receiving somatostatine), no information on dose or on potential adverse effects was reported. Infants treated with octreotide/somatostatin had similar mortality compared with those not receiving any of these drugs. The duration of pleural drainage was longer, and administration of antithrombin as well as blood culture-positive sepsis was more frequent with octreotide/somatostatin treatment (table 2). Infants receiving such treatment tended to have longer hospital stays, longer duration of respiratory support and higher pleural drainage output. Six infants had been cared for in our institution, a large tertiary referral centre; two receiving octreotide. Analysing these six versus all other infants born in Germany in 2012 revealed no significant differences (data not shown).
DISCUSSION The incidence of CCT has previously been estimated between 1:7300 and 1:10 000 live births.5 6 9 These estimates were not population based. In our study, the incidence of CCT was only 1:24 000. This difference between estimates is likely due to different study designs, but our investigation may also have been
Table 1 Treatment and outcome data of infants with congenital chylothorax Demographic variable
N
Prenatal diagnosis Prenatal intervention Absolute leucocyte count in pleural effusion (1/mL) Relative lymphocyte count in pleural effusion (%) Any postnatal iNO treatment Duration of iNO treatment (days) Any blood culture-positive sepsis Any antibiotic therapy Duration of antibiotic therapy (days) Discharged home on medium-chain triglyceride diet Any surgical intervention Any OK-432 administration into pleura
27 27 23 18 26 26 27 26 26 20 27 27
23 (85%) 12 (44%) 2900 (65–47 230) 93.5 (76–99) 5 (19%) 2 (2–7) 6 (22%) 26 (100%) 13,5 (0–44) 13 (65%) 0 (0%) 0 (0%)
Data are presented as median (range) or n (%). The number of infants (N) in whom data were provided is given for each item. iNO, inhaled nitric oxide.
Bialkowski A, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F169–F172. doi:10.1136/archdischild-2014-307274
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Short research report Table 2 Infants with congenital chylothorax treated with octreotide/somatostatine versus those not receiving peptide hormone treatment
Birth weight (g) Gestational age at birth (weeks) Mortality Underlying genetic anomaly Duration of mechanical ventilation (days) Duration of continuous positive airway pressure (days) Duration of any respiratory support (days) Duration of pleural drainage (days) Total drainage output (mL) Length of hospital stay (days) Clinical sepsis Blood culture-positive sepsis Substitution of antithrombin Discharged on medium-chain triglyceride diet
Octreotide/somatostatin
No peptide hormone
p Value
2440 (1820–3800) 33.4 (30.0–39.1) 0/9 2/9 13.5 (3–105) 8.5 (1–14) 19.5 (10–107) 16 (7–36) 1802 (50–10 200) 59 (28–127) 7/9 5/9 4/9 5/7
2522 (740–3940) 33.9 (24.7–37.4) 3/18 7/18 4 (0–37) 4 (0–29) 15 (0–38) 9 (0–29) 581 (0–4504) 43 (20–83) 7/18 1/18 1/18 8/12
0.29 0.53 0.19 0.38 0.20 0.93 0.19 0.03 0.13 0.33 0.056 0.003 0.014 0.83
Data are presented as median (range) or n/N.
susceptible to chance variability in incidence because of its relatively short observational period of 12 months. Furthermore, incomplete reporting for fear that each reported case will entail a questionnaire that has to be filled in may have resulted in a falsely low incidence. In contrast, regular audits of ESPED’s return rate for completed questionnaires consistently exceeded 93%.14 Haines et al have reported a similar return rate for their chylothorax survey in the UK.15 A male/female ratio of 2:1 reported in other studies9 16 concurs with our findings; the reason for this is unknown. To ensure complete reporting, paediatric departments were asked to report all non-traumatic pleural effusions with relative lymphocyte counts as low as 60% (rather than the 80% reported in the literature). However, 17/18 infants with report on relative lymphocyte counts had >80% lymphocytes in their pleural effusion and the lowest value reported was 76%, well in agreement with the literature. In previous case series, mortality was around 15–20%,9 17 whereas mortality in this cohort was 11% and largely explained by existing comorbidities. Decreased mortality may reflect more comprehensive prenatal and postnatal management in recent years. In our study, 26 of 27 cases were detected antenatally, of which 12 were treated in utero by pleural puncture or pleural drainage, but the safety and efficacy of prenatal interventions yet needs to be elucidated. Postnatal treatment was, on the one hand, supportive, that is, included treatment of respiratory distress (by mechanical ventilation and drainage of the pleural effusion), complications (hypotension; systemic infection) and substitution of pleural losses (with albumin, immunoglobulins or antithrombin). On the other hand, reduction in chylous production was attempted either by withholding enteral nutrition and providing total parenteral nutrition, or by feeding an MCT diet.2 18 19 In the past, beneficial effects of octreotide or somatostatine on chylous fluid production have been claimed in several case series.20–22 Our data suggest that patients treated with these drugs were more seriously ill (see table 2), with significantly longer duration of pleural drainage and more infants with blood culture-positive sepsis or antithrombin administration. However, efficacy of this treatment needs to be evaluated in a prospective interventional trial. Safety of peptide hormone treatment has never been prospectively evaluated in newborns with CCT. So far, necrotising enterocolitis (NEC),23 transient hypothyroidism,6 transient
increases in liver enzymes24 and hyperglycaemia have been reported in CCT infants treated with these peptide hormones. Isolated, that is, non-NEC-associated bloody stools may need to be added to the list of potential side effects because these had been reported once, several days after discontinuation of peptide hormone treatment, with spontaneous resolution. Published dosing regimens for octreotide and somatostatine are quite variable.17 22 As expected, this is also evident in our data, reflecting insufficient knowledge on peptide hormone pharmacokinetics in infants with CCT. Based on this prospective epidemiological study, the clinical management approach in Germany seems to be quite heterogeneous. Several years prior to this study, we established a standardised treatment algorithm at our institution, quite similar to the one recently reported by Downie et al16 for CCT or by Panthongviriyakul and Bines25 for postoperative chylothorax. But to date, no standardised approach has been evaluated prospectively and there is yet no evidence that this standardised approach results in improved outcome. Again, the observational design and the small sample size of our study prohibit any firm conclusions. In summary, we report prospective population-based epidemiological, treatment and outcome data on CCT. The incidence of CCT found here was smaller than expected—and although outcome is mostly favourable, it is unclear to what extent treatment modalities actually improve outcome. We agree with Bellini et al17 that there is an evident need for an international multicentre trial including long-term follow-up. Contributors AB performed the study. She collected all clinical data and analysed it with the support of ARF and wrote the first draft of the manuscript. ARF contributed to the manuscript and performed the statistical analyses. CFP contributed to the manuscript and helped to design the study. AB and ARF designed the study and wrote the ethics submission. Competing interests None. Ethics approval Ethical Board of University of Tuebingen, Germany. Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES 1 2 3
Staats BA, Ellefson RD, Budahn LL, et al. The lipoprotein profile of chylous and non chylous pleural effusions. Mayo Clin Proc 1980;55:700–4. Straaten van HL, Gerards LJ, Krediet TG. Chylothorax in the neonatal period. Eur J Pediatr 1993;152:2–5. Büttiker V, Fanconi S, Birger R. Chylothorax in children: guidelines for diagnosis and management. Chest 1999;116:682–7.
Bialkowski A, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F169–F172. doi:10.1136/archdischild-2014-307274
F171
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Short research report 4 5 6
7 8 9 10
11
12 13
14
F172
Chernick V, Reed MH. Pneumothorax and chylothorax in the neonatal period. J Pediatr 1970;76:624–32. Ergaz Z, Bar-Oz B, Yatsiv I, et al. Congenital chylothorax: clinical course and prognostic significance. Pediatr Pulmonol 2009;44:806–11. Maayan-Metzger A, Sack J, Mazkereth R, et al. Somatostatin treatment of congenital chylothorax may induce transient hypothyroidism in newborns. Acta Paediatr 2005;94:785–9. Goens MB, Campbell D, Wiggins JW. Spontaneous chylothorax in Noonan syndrome. Am J Dis Child 1992;146:1453–6. Paget-Brwon A, Kattwinkel J, Rodgers BM, et al. The use of octreotide to treat congenital chylothorax. J Pediatr Surg 2006;41:845–7. Rocha G, Fernandez P, Rocha P, et al. Pleural effusions in the neonate. Acta Paediatr 2006;95:791–8. Moerman P, Vandenberghe K, Devlieger H, et al. Congenital pulmonary lymphangiectasis with chylothorax: a heterogeneous lympathic vessel abnormality. Am J Med Genet 1993;47:54–8. Bellini C, Ergaz Z, Boccardo F, et al. Dynamics of pleural effusion and chylothorax in the fetus and newborn: role of the lymphatic system. Lymphology 2013;46:75–84. ESPED Bericht [ESPED report] Monatszeitschrift Kinderheilkunde 10, Oct 2013, p964. Statistisches Bundesamt, Geburtentrends und Familiensituation in Deutschland. 2012. (Statistical department and family situation in Germany 2012) https://www. destatis.de/DE/Publikationen/Thematisch/Bevoelkerung/HaushalteMikrozensus/ Geburtentrends5122203129004.pdf?__blob=publicationFile (accessed 3 Jul 2014). Gobel U, Heinrich B, Krauth KA, et al. Process and outcome quality of the German Paediatric Surveillance Unit (ESPED). Klin Padiatr 2010;9:92–7.
15 16 17
18 19
20
21 22 23
24
25
Haines C, Walsh B, Fletcher M, et al. Chylothorax development in infants and children in the UK. Arch Dis Child 2014;99:724–30. Downie L, Sasi A, Malhotra A. Congenital chylothorax: associations and neonatal outcomes. J Paediatr Child Health 2014;50:234–8. Bellini C, Ergaz Z, Radicioni M, et al. Congenital fetal and neonatal visceral chylous effusions: neonatal chylothorax and chylous ascites revisited. A multicenter retrospective study. Lymphology 2012;45:91–102. Beghetti M, La Scala G, Belli D, et al. Etiology and management of pediatric chylothorax. J Pediatr 2000;136:653–8. Fernandez Alvarez JR, Djaffar Kalache K, Gruel EL. Management of spontaneous congenital chylothorax: oral medium-chain triglycerides versus total parenteral nutrition. Am J Perinatal 1999;16:415–20. Roehr CC, Jung A, Proquitte H, et al. Somatostatin or octreotide as treatment options for chylothorax in young children: a systematic review. Intensive Care Med 2006;32:650–7. Das A, Shah PS. Octreotide for the treatment of chylothorax in neonates. Cochrane Database Syst Rev 2007;(9):CD006388. Helin RD, Angeles STV, Bhat R. Octreotide therapy for chylothorax in infants and children: a brief review. Pediatr Crit Care Med 2006;7:576–9. Mohseni-Bod H, Macrae D, Slavik Z. Somatostatin analog (octreotide) in management of neonatal postoperative chylothorax: is it safe? Pediatr Crit Care Med 2004;5:356–7. Demirbilek H, Shah P, Arya VB, et al. Long-term follow-up of children with Congenital Hyperinsulinism on Octreotide Therapy. J Clin Endocrinol Metab 2014;99:3660–7. Panthongviriyakul C, Bines JE. Post-operative chylothorax in children: an evidence-based management algorithm. J Paediatr Child Health 2008;44:716–21.
Bialkowski A, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F169–F172. doi:10.1136/archdischild-2014-307274
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Congenital chylothorax: a prospective nationwide epidemiological study in Germany Anja Bialkowski, Christian F Poets, Axel R Franz and and the Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland Study Group Arch Dis Child Fetal Neonatal Ed 2015 100: F169-F172 originally published online December 5, 2014
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