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Controversies in the management of cystic lung disease
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[27] Teper AM, Marcos CY, Theiler G, Colom AJ, Fainboim L. Association between HLA and the incidence of bronchiolitis obliterans (BO) in Argentina. Am J Respir Crit Care Med 2004; 169: 382 (Abstract). [28] Teper A, Colom A, Bailliet G, Martnez-Marignac V, Bianchi N. Association between the incidence of bronchiolitis obliterans (BO) in Argentine children and their native-american maternal and paternal lineage. Am J Respir Crit Care Med 2003; 167: 998. (Abstract.) [29] Kajon A, Gigliotti A, Harrod K. Acute inflammatory response and remodeling of airway epithelium after subspecies B1 human adenovirus infection of the mouse lower respiratory tract. J Med Virol 2003; 71: 233–244. [30] Leong MA, Nachajon R, Ruchelli E et al. Bronchitis obliterans due to Mycoplasma pneumonia. Pediatr Pulmonol 1997; 23; 375–338. [31] Massie R, Armstrong D. Bronchiectasis and bronchiolitis obliterans post respiratory syncytial virus infection: think again. J Paediatr Child Health 1999; 35: 497–498. [32] Hirschheimer M, Silva P, Giudici R et al. Simultaneous viral infection and childhood bronchiolitis obliterans. Braz J Infect Dis 2002; 6: 146– 148. [33] Swyer PR, James GCW. A case of unilateral pulmonary emphysema. Thorax 1953; 8: 133–136. [34] MacLeod VVM. Abnormal transradiancy of one lung. Thorax 1954; 9: 147–153. [35] Leung A, Fisher K,Valentine V, Girgis R, Berry G, Robbins R, Theodore J. Bronchiolitis obliterans after lung transplantation, detection using expiratory HRCT. Chest 1998; 113: 365–370. [36] Teper AM, Kofman CD, Maffey AF et al. Lung function in infants with chronic pulmonary disease after severe adenoviral illness. J Pediatr 1999; 134: 730–733. [37] Maffey A, Colom A, Kofman C, Vidaurreta S, Teper A. Longitudinal study of pulmonary function in infants with post viral chronic pulmonary disease (PCPD). Am J Respir Crit Care Med 1996; 153: 498. (Abstract.) [38] Colom AJ, Maffey A, Navarra F, Teper A. Pulmonary function in children with post-viral chronic pulmonary disease (PCPD). Am J Respir Crit Care Med 2002; 163: A159. (Abstract.) [39] Colom AJ, Navarra F, Kofman C, Teper A. Respiratory mechanics in children with post-viral chronic pulmonary disease (PCPD). Am J Respir Crit Care Med 2002; 163: A159. (Abstract). [40] Kim CK, Kim SW, Kim JS et al. Bronchiolitis obliterans in the 1990s in Korea and the United States. Chest 2001; 120: 1101–1106. [41] Fullmer J, Fan L, Dishop M, Rodgers C, Krance R. Successful treatment of bronchiolitis obliterans in a bone marrow transplant patient with tumor necrosis factor-a blockade. Pediatrics 2005; 116: 767–770. [42] Gerhardt S, McDyer J, Girgis R, Conte J, Yang S, Orens J. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome. Results of a pilot study. Am J Respir Crit Care Med 2003; 168: 121–125. [43] Colom A and Teper AM. Clinical prediction rule to diagnose postinfectious bronchiolitis obliterans in children. Pediatr Pulmonol 2009; 44:1065–1069.
General Topics Lung Development and Related Respiratory Pathologies 10:20–11:50
Room C
O.4.1 Advances in lung development A.A. Hislop. Institute for Child Health, UCL, 30 Guilford St, London WC1N 1EH, United Kingdom Correspondence: #447 (0)207 905 2337, #44 (0)207 813 8459. E-mail: [email protected]
The description of the developing lung is well known. The primary goal is to produce a large gas exchange area within a relatively small volume of thorax. It appears in the 4th week of gestation and by a process of branching morphogenesis the entire bronchial tree is present by the 16th week of gestation. Alveoli are first formed in the last 10 weeks of gestation and they continue to form for at least 2–3 years after birth. Blood vessels appear alongside the airways and alveoli as they form by vasculogenesis and angiogenesis. Many influences in utero and childhood will lead to a restriction of normal growth and it is accepted that reduced lung function at birth and
in early childhood tracks into adulthood. Studies on the control of normal and abnormal growth should give us clues as to how we may repair abnormal lungs and it is this field that is showing the most advances at the moment. Throughout lung development there is interaction of many growth factors and transcriptional factors. In addition to these genetic influences there are the physical effects of space, fluid, nutrition and environment which includes oxygen tensions and maternal smoking. Since airway development is complete early in gestation it is unlikely that any abnormalities in airway numbers can be reversed. However alveolar development continues postnatally and it is the encouragement of new alveolar growth which is studies most using experimental models. Post pneumonectomy or lobectomy there is increase in lung volume of the residual lung to fill space. This can be a very rapid response. In adult dogs HIF-1a and vascular endothelial growth factor are increased after only 3 days. Both of these are known to promote angiogenesis and alveolar formation. Maternal food restriction and deficiency of Vitamin A and D lead to abnormal lungs in man and other species. In experimental animals supplemental feedings can restore alveolar growth again very rapidly. Repair in the airways is largely due to the basal cells of the epithelium while in the alveolar region it is the Type II alveolar cells. However there are also bronchioalveolar stem cells and a pluripotent side population of cells derived from the bone marrow. Circulating endothelial progenitor cells can also promote capillary formation. The combination of these can lead in animals to formation a new alveoli. Reference(s) Baraldi E, Filippone M, N Engl J Med 2007: 357, 1946–55 Van Haaften T, Thebaud B, Pediatr Res 2006: 59, 94R-99R
O.4.2 Controversies in the management of cystic lung disease A. Bush1,2 . 1 Paediatric Respirology, Imperial School of Medicine at National Heart and Lung Institute; and 2 Royal Brompton Hospital, UK Correspondence: A. Bush. Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Tel: 207 351 8232; fax: 207 351 8763. E-mail: [email protected] Keywords: Sequestration, bronchogenic cyst, congenital cystic adenomatoid malformation, fetal surgery, hydrops, sarcoma, pleuropulmonary blastoma
Abstract: The antenatal diagnosis of a congenital thoracic malformation (CTM) leads to anxiety and uncertainty as to best management. CTM comprises congenital cystic adenomatoid malformation, sequestration, congenital lobar emphysema, enteric and bronchogenic cysts, and bronchial atresia. Most require only observation antenatally, and reduce in size substantially in the third trimester. If fetal hydrops develops, then antenatal intervention, usually surgical, is required, because untreated mortality is high. If the baby is symptomatic in the newborn period, then surgical intervention is clearly needed. The treatment of the asymptomatic baby is the major controversial area. Advocates of early surgery point to the complications of CTM, which include infection, pneumothorax, bleeding and malignant transformation. The proponents of conservative management retort that some CTMs disappear postnatally, and that the complication rate is unknown; many children appear never to need surgery. Furthermore, excision of a CTM does not totally eliminate the risk of a subsequent malignancy. Counselling of the family on a case by case basis is needed, both antenatally and postnanatally, stressing the limitations of present evidence. Introduction: There is not enough evidence to give definite opinions to parents of a foetus in whom a congenital thoracic malformation (CTM) has been discovered. We do know that: 1. Many antenatally diagnosed CTMs will regress spontaneously before birth. Thus any fetal intervention runs the risk of being unnecessary and meddlesome. Rare cases of true spontaneous postnatal regression of a CTM have been recorded [1].
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2. If the child is significantly symptomatic in the newborn period despite medical management, then surgery is indicated. However, an asymptomatic infant who is offered surgery will be being exposed to a small risk of iatrogenic complications. 3. There are late complications of CTMs, including infection, pneumothorax, malignant transformation, high output cardiac failure and air embolism, but the risk is unkown. Malignant transformation is not always preventable by resection. This review focuses briefly on the ante- and post-natal nomenclature to use in discussions, the antenatal presentations of CTMs, and the ante- and post-natal options with their advantages and disadvantages, concluding with a suggested practical approach to parents. These may be contrasted with other recent reviews [2,3]. Amongst the problems of making sense of the literature are the diversity of the histological patterns, and the rarity of the lesions, estimated at between 1 in 20–30,000 live births [4]. Later post-natal presentations of CTMs, and a detailed account of their pathology, are discussed in detail elsewhere [5]. Nomenclature of CTMs: The nomenclature of congenital lung disease has been confusing for the following reasons. 1. Sequestration and cystic adenomatoid malformation (CCAM) are often assumed to be separate identities, and pathologically have distinct features, but histological features of both may be found within the same lesion (‘Hybrid lesions’). 2. There is inconsistent use of nomenclature before and after birth. For example, the term CCAM is used by perinatologists to describe a lesion that may well disappear before birth, but is used postnatally to describe an abnormality which often but not invariably requires lobectomy. 3. No matter how sophisticated the imaging modality used, the clinician can only see shades of grey, and should not make unwarranted pathological assumptions from these pictures. The same clinical appearance (e.g., a multicystic mass) may have one of several different histological appearances when excised. 4. The pathologist who can examine the excised lesion, and can provide a precise account of what it contains, quite different from the clinician. It is suggested that the following principles should be followed when looking at clinical images, either antenatally or postnatally [6]: a. What is actually seen should be described, without embryological or pathological speculation, which may later be proved wrong. A simple ‘catch-all’ term, congenital thoracic malformation (CTM) has been proposed to replace the old nomenclature in clinical discussions [6], because this makes no pathological assumptions. The spectrum of CTM includes CCAM, sequestration, bronchogenic and foregut cysts, and bronchial atresia with distal cystic degeneration [7]. Postnatally at least, a congenital large hyperlucent lobe (CLHL, “congenital lobar emphysema” is separated off, because late complications are almost unknown; antenatally, CLHL may be impossible to distinguish from other pathological causes of CTM b. The description should be in simple clear language. Thus a CTM could described (antenatally or postnatally) as solid or cystic; if cystic, the cysts should be described as single or multiple, whether large or small (ideally with the size measured rather than estimated), thin or thick walled, and whether the contents are purely fluid or (postnatally) they contain air should also be noted. Speculating about pathology from antenatal ultrasound scans often leads to a revision of the diagnosis once the lesion has been resected [8] c. The rest of the respiratory system should be described in a systematic manner as far as possible, in particular the arterial and venous trees. d. Other organs should be considered systematically, because associated lesions will be missed unless carefully sought. Antenatal presentations of CTMs: Most abnormalities are detected around 20 weeks’ gestation, at the routine fetal anomaly scan,
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either from an abnormality of amniotic fluid volume or the discovery of a mass. CTMs can cause polyhydramnios in isolation as a result of compression of the fetal esophagus preventing the swallowing of amniotic fluid, or as part of fetal hydrops. A mass (cystic or solid) may be directly identified in the fetal thorax or its presence may be suspected because of mediastinal shift. Increasingly, fetal MRI is being used further to image suspected lesions and the surrounding lung [9–13]. MRI can confirm the presence of the mass, delineate the blood supply, and help to assess the residual lung parenchyma [9,10], although the place of this technique remains to be determined. Cystic CTMs usually occur alone, although other associated abnormalities have been described, including bronchopulmonary sequestration, congenital diaphragmatic hernia and extrapulmonary malformations including renal and cardiac anomalies, but not aneuploidy [14,15]. A so-called fetal sequestrated lobe is most often identified as an echogenic mass of uncertain origin in the chest or sub-diaphragmatic area; demonstration of an aortic blood supply, usually by colour flow Doppler, is not diagnostic, because a CCAM may also have an aortic blood supply (above). The results of investigation may result in fetal therapy being offered (below), or more usually, identifies fetuses that should be delivered in a centre offering high level neonatal intensive care where early postnatal surgery can be performed if needed. Where any lesion has persisted or increased in size and mediastinal shift persists in the third trimester, delivery in such a centre is advisable. Options for antenatal management of CTMs: a paediatric perspective: The first big question is, is any antenatal intervention warranted at all? The prognosis for a fetus with a cystic CTM (“CCAM”) is generally good; the lesion tends to peak in size at 25 weeks, and then regress [16]. One series of 48 CTMs [17] reported that in 22 cases, the lesions disappeared, and only 6 became severe. Another group reported that 64 of 67 fetuses with an antenatally diagnosed CTM were born alive, of whom 42 underwent postnatal surgery [18]. Accurate prediction of outcome can be difficult on a single scan, and serial scans should be undertaken to detect lesions which are not regressing. Antenatal ultrasound features which were predictive of hydrops were MTR (ratio of mass size to thorax size), cystic predominance, and diaphragmatic eversion; these fetuses need particularly careful follow-up [19]. Protocols for ultrasound follow-up have been described [20]. MRI can be used to calculate CTM volume to head ratio (CVR) [21]; a ration of ≥1.6 is 80% predictive of progression to hydrops, whereas CVR ≤1.6 had a good prognosis (only 2% becoming hydropic). CTMs with a single dominant cyst may behave unpredictably, and MRI should be interpreted with caution in this context. However, all the series to 2007, which were summarised in [22], and additional series published since then [2,20,23] have confirmed the key message, that only a tiny minority of antenatally diagnosed CTMs will require antenatal intervention. However, equally clear is that if the fetus becomes hydropic, mortality without intervention is close to 100% [24], but this can be improved by a number of interventions [25,26]. It should be noted that there are rare but well documented cases of CTMs causing hydrops which have resolved spontaneously [27]. A very rare complication is ‘maternal mirror syndrome’ [28–30], in which rapid development of pre-eclampsia, proteinuria and pulmonary oedema herald maternal death unless fetus and placenta are urgently delivered. If intervention is needed, the options which have been proposed include cyst decompression or pleuro-amniotic shunting for in particular isolated pleural effusion, intra-uterine surgery or sclerotherapy, embolization of collateral vessels, radiofrequency ablation, and maternal steroid therapy. For the most part, experience is limited to small case series, and there are no controlled clinical trials. There are anecdotal reports of the use of maternal injections of betamethasone in fetal CTM with better outlook than historical controls [31,32]. Around 50% of hydropic fetuses may respond to maternal betamethasone [33]. However, an unexpected
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intra-uterine death has been reported after resolution of hydrops following betamethasone therapy [34]. Furthermore, the response is very variable, and, if the CTM progresses despite a first course of steroids, then further courses are not useful, and surgical management is required [33], although this is disputed [34]; clearly more data are needed. There are many surgical options. Where there are single or multiple large cysts with associated hydrops or polyhydramnios improvement has been reported with in-utero decompression by thoracocentesis or the insertion of a pleuroamniotic shunt [20,36,37]. Shunting is only beneficial in the setting of antenatal CTM when there is pleural effusion or fetal hydrops [37]. The prognosis for shunted CTMs containing a dominant large cyst is good, even if there is hydrops, with around 75% survival [38]. It may be complicated by later chest deformity, particularly if shunting is performed at less than 21 weeks gestation [36]. This contrasts with the results of fetal surgery, also occasionally used in these lesions [20], where the incision heals in utero without leaving a scar. Other techniques reported in small series include sclerotherapy of abnormal feeding vessels, and sclerotherapy of the mass under ultrasound control [39,40]. If the feeding vessel is occluded by fetal sclerotherapy, around half the fetuses will need no further postnatal treatment [2]. A case in which radiofrequency ablation was used [19] to ablate a large CTM resulted in fetal death, presumed to be due to hemorrhage into the necrotic mass. This case would suggest cautious use of any procedure, either ante- or post-natal, which results in infarction of the mass. Options for postnatal management of CTMs: a paediatric perspective: At the most dramatic end of the spectrum, a fetus with a huge malformation severely compromising the airway will require ex-utero, intrapartum treatment (EXIT procedure) [41]. Similarly, the baby who is symptomatic with a large CTM or CLHL will require treatment in the neonatal period; very occasional big malformations require EXIT to resection on placental support [41]. If less severely affected babies nonetheless remain too tachypnoeic to feed, or are severely stridulous because the airway is compressed by the CTM, or are less severely tachypnoeic but fail to thrive, then surgical treatment is inevitable. For many abnormalities, surgery is the best and definitive treatment; occasionally a lesser procedure such as embolization of a feeding vessel may be all that is needed [42]. If pulmonary hypertension complicates a CTM, then stabilization prior to surgery is preferable [43]. Symptomatic babies undergoing surgery in the newborn period have a higher complication rate than asymptomatic infants [44]. For all but the smallest, sickest infants, lobectomy is a safe and well tolerated procedure, with few if any significant sequelae. Increasingly, this is performed thoracoscopically; the inpatient stay and duration of placement of chest drains is shorter [45]; however preceding pneumonia may mandate conversion of thoracoscopy to formal thoracotomy [46], which is a consideration when deciding whether to defer surgery in the asymptomatic child (below). The minimal possible resection should be performed [47]. However, pneumonectomy carries a significant mortality in infancy. There is also considerable long term morbidity, in particular scoliosis which may worsen dramatically during the pubertal growth spurt. What to do for the baby who is well and thriving, but who has been given an antenatal diagnosis of a CTM, is completely unclear. They should have a CXR prior to discharge. In many it will be normal, but subsequent, more detailed imaging may reveal malformations; CXR was only 61% sensitive for malformations, compared with the gold standard of HRCT [48]. There were no false positive diagnoses on HRCT. However the unanswerable and related questions that arise are (1) what further imaging should be performed; and (2) should such infants be submitted to surgery, and if so, when? The question of surgery has to be dealt with first, because clearly here is little point in requesting a HRCT in a very young child if no action will be taken on the results. Surgery for asymptomatic CTMs is a really controversial area. If the lesion is cystic, then it is likely (but unproven) that infection
will occur sooner or later, and some would advise prophylactic excision [49]. It is said that all lesions should be excised to prevent malignant transformation, but there definitive evidence against this view (below). Other rare complications, which would definitely be prevented by surgery include bleeding into or from the cysts, pneumothorax, and air embolism [50–54]. Whether an asymptomatic malformation should be resected to facilitate normal lung growth is not clear. The advocates of an aggressive approach argue that an asymptomatic CTM merits surgery because it is likely that there will be a complicating infection of the cyst eventually, which may make the operation more difficult, sometimes mandating conversion of VATS to a thoracotomy [46,49]. Furthermore, in one series, 50% of CTMs resected after the age of six months were thought to show evidence of chronic infection [48], a higher prevalence than I have seen in my practice. Anecdotally, I have seen a single child who was thought to be asymptomatic, and had a large CTM removed which on histology showed evidence of chronic infection. Post-operatively, the child was much happier and healthier than before, and the parents realized that in fact the child had been a lot less well prior to surgery than they had thought. However, this has been the exception in my experience. Another challenging observation is that there is evidence of chronic inflammation even in most CTMs, even those which were resected very early in life [52]. Again, the practical significance of this is hard to determine. Finally, in one very small series (as with all others, uncontrolled) those initially treated conservatively, and then subsequently undergoing surgery had a longer operation time and greater blood loss, but were not otherwise disadvantaged [55]. Surgery is generally uncomplicated [56]. In favor of conservative management is the fact that some lesions may regress completely post-natally [1,53]. Furthermore, data presented briefly in a letter to the Editor suggested that in more than 100 malformations, 10% required surgery in the newborn period, a further 5% became infected and subsequently had an operation, and 85% remained symptom free with no surgery; the detailed duration of follow-up is not stated [576]. Others report a much higher proportion of children requiring surgery [50,51], many as an emergency. These children tended to need larger resections, although whether this was because of emergency presentation is not clear. A Canadian survey highlighted that even among surgeons there was no consensus about whether to operate on an asymptomatic CTM, what procedure to do and when to do it. Of interest, 80% of CTMs managed conservatively initially eventually underwent surgery; however, it is not clear from the manuscript what proportion became symptomatic, and how many underwent surgery because of peer or parental pressure [58]. If the risk of these lesions becoming infected is unknown, still less do we know the risk of malignant transformation. The following facts are clear. • Primary pulmonary malignancy in childhood is very rare, and the evidence that there is in fact an increased risk in most types of CTM is tenuous [3] • There are case reports and case series of co-existence of CTM and a variety of primary pulmonary malignancies [59– 71]. These include bronchioloalveolar carcinoma and Type 1 CCAM [61,68,71]; pleuropulmonary blastoma (PPB) and Type 4 CCAM [62], and PPB and a congenital lung cyst [65]; CCAM (type unspecified) and rhabdomyosarcoma [66,67]. Further information on the relationship between CCAM and PPB can be found at www.ppbregistry.org. • Even complete removal of a CTM cannot prevent the development of malignant disease elsewhere in the lung [69,72,73], implying that the malformation is merely a marker of increased malignant potential throughout the lungs, in which case removing the malformation would not deal with the underlying problem. Thus although one group [74] suggested on the basis of cytogenetic and p53 profiles that CCAM was not a premalignant condition, the rest of the literature is less reassuring. It is suggested that a higher
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incidence of suspicion is justified in those with bilateral disease, a family history of pleuropulmonary blastoma, pulmonary cysts or renal anomalies, or a close relative with a childhood malignancy, especially Wilm’s tumour or medulloblastoma. The registry data on the relationship of pleuropulmonary blastoma and CTM has been reviewed [75]. Malignant transformation is rare, but more evidence is needed. Thus we do not know the risk of infection or malignant transformation. Surgery prevents infection, although cysts recurrence has been described [50], but it does not always prevent pulmonary malignancy. If surgery is contemplated, it is essential to delineate the anatomy of the CTM, and in particular the blood supply. HRCT scanning after contrast, with modern reconstruction techniques is used to delineate the blood supply and venous drainage CTM [76]. MRI may also be used. What to say to the parents: a practical approach: If a large CTM is discovered at the 20 week anomaly scan, then parental anxiety is likely to be huge; almost paradoxically parents worry more about the uncertainty around a usually benign prognosis CTM than about definitively bad prognosis lesions such as congenital diaphragmatic hernia [77]. Parents should be advised that the vast majority of CTMs require no antenatal intervention, and the likeliest outcome is the safe delivery of a healthy infant, for whom an elective operation may need to be considered at some stage. Early consultation with respiratory paediatricians and paediatric surgeons is helpful. Progress is followed with serial ultrasound scans. Parents of the rare fetus requiring antenatal intervention should receive counselling from a specialist perinatologist. My personal, non-evidence based practice is to recommend postnatal surgery for all but trivial CTMs, so that an elective, low risk procedure can be performed at a convenient time, rather than the possibility of having to deal as an emergency with an infected malformation. If the child is well and thriving, I perform HRCT without contrast in the first few weeks of life; if the CTM has truly involuted, or of trivial size, then no further action is needed. If the size is significant, then timing of surgery is a trade-off between allowing the baby to grow, and not allowing time for complications to develop. Since complications are rare before age 2 years [55] (although definitely described [78]) I advise surgery towards the end of the second year of life. However, there is recent, albeit indirect evidence from post-operative nuclear medicine studies that lung growth postoperatively may be better if surgery is performed before a year of age, in uninfected children [79]. Interestingly, the size of resection was apparently irrelevant. In preparation for surgery, I recommend a second HRCT scan with contrast at 18 months of age; if the mass has involuted, surgery is cancelled. Immediate surgery in the postnatal period may mean some children will undergo an unnecessary operation. It could be argued that the first HRCT is unnecessary, but it allows some infants to be discharged immediately; furthermore, if the CTM is in fact a CLHL (“congenital lobar emphysema”) and the child is asymptomatic, then the family can be reassured that surgery is highly unlikely ever to be necessary, since these lesions do not become infected, and no further imaging is required. In summary, given the lack of evidence, at all stages the paediatrician would do well to share with the parents the little that is known, and the large amount that is unknown, and discuss the lesions with the family on a case by case basis [80]. Reassuringly, whatever options are chosen, the long term outlook for the vast majority is excellent. Reference(s) [1] Nagata K, Masumoto K, Tesiba R, Esumi G, Tsukimori K, Norio W, Taguchi T. Pediatr Surg Int. 2009 Aug 7. [Epub ahead of print.] [2] Cavoretto P, Molina F, Poggi S, Davenport M, Nicolaides KH. Prenatal diagnosis and outcome of echogenic fetal lung lesions. Ultrasound Obstet Gynecol. 2008; 32: 769–83.
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[3] Lakhoo K. Management of congenital cystic adenomatous malformations of the lung. Arch Dis Child Fetal Neonatal Ed. 2009; 94: F73–6. [4] Laberge JM, Flageole H, Pugash D, Khalife S, et al. Outcome of the prenatally diagnosed congenital cystic adenomatoid lung malformation: a Canadian experience. Fetal Diagn Ther 2001; 16: 178–86. [5] Abel R, Bush A, Chitty L, Harcourt J, Nicholson A. Congenital lung disease. In: Chernick V, Boat T, Wilmott R, Bush A (Eds). Kendig’s Disorders of the Respiratory Tract in Children. 7th Edition, Publ Elsevier, 2006, pp 280–316. [6] Bush A. Congenital lung disease: a plea for clear thinking and clear nomenclature. Pediatr Pulmonol 2001; 32: 328–337. [7] Tsai AY, Liechty KW, Hedrick HL, Bebbington M, Wilson RD, Johnson MP, Howell LJ, Flake AW, Adzick NS. Outcomes after postnatal resection of prenatally diagnosed asymptomatic cystic lung lesions. J Pediatr Surg. 2008 Mar;43(3):513–7. [8] Kuroda T, Morikawa N, Kitano Y, Sago H, Hayashi S, Honna T, Saeki M. Clinicopathologic assessment of prenatally diagnosed lung diseases. J Pediatr Surg. 2006; 41: 2028–31. [9] Bulas D. Fetal magnetic resonance imaging as a complement to fetal ultrasonography. Ultrasound Q 2007; 23: 3–22. [10] Laifer-Narin S, Budorick NE, Simpson LL, Platt LD. Fetal magnetic resonance imaging: a review. Curr Opin Obstet Gynecol. 2007; 19: 151–6. [11] Barnewolt CE, Kunisaki SM, Fauza DO, Nemes LP, Estroff JA, Jennings RW. Percent predicted lung volumes as measured on fetal magnetic resonance imaging: a useful biometric parameter for risk stratification in congenital diaphragmatic hernia. J Pediatr Surg. 2007; 42: 193–7. [12] Kasprian G, Balassy C, Brugger PC, Prayer D. MRI of normal and pathological fetal lung development. Eur J Radiol. 2006; 57: 261–70. [13] Cannie MM, Jani JC, Van Kerkhove F, Meerschaert J, De Keyzer F, Lewi L, Deprest JA, Dymarkowski S. Fetal Body Volume at MR Imaging to Quantify Total Fetal Lung Volume: Normal Ranges. Radiology. 2008 Feb 7; [Epub ahead of print.] [14] Samuel M, Burge DM. Management of antenatally diagnosed pulmonary sequestration associated with congenital cystic adenomatoid malformation. Thorax 1999; 54: 701–706. [15] Thorpe-Beeston JG, Nicolaides KH, Cystic adenomatoid malformation of the lung: Prenatal diagnosis and outcome. Prenat Diagn 1994; 14:677– 688. [16] Kunisaki SM, Barnewolt CE, Estroff JA, Ward VL, Nemes LP, Fauza DO, Jennings RW. Large fetal congenital cystic adenomatoid malformations: growth trends and patient survival. J Pediatr Surg. 2007; 42: 404–10. [17] Illanes S, Hunter A, Evans M, Cusick E, Soothill P. Prenatal diagnosis of echogenic lung: evolution and outcome. Ultrasound Obstet Gynecol. 2005; 26: 145–9. [18] Davenport M, Warne SA, Cacciaguerra S, Patel S, Greenough A, Nicolaides K. Current outcome of antenatally diagnosed cystic lung disease. J Pediatr Surg 2004; 39: 549–56. [19] Vu L, Tsao K, Lee H, Nobuhara K, Farmer D, Harrison M, Goldstein RB. Characteristics of congenital cystic adenomatoid malformations associated with nonimmune hydrops and outcome. J Pediatr Surg. 2007; 42:1351–6. [20] Azizkhan RG, Crombleholme TM. Congenital cystic lung disease: contemporary antenatal and postnatal management. Pediatr Surg Int. 2008; 24: 643–57. [21] Crombleholme TM, Coleman B, Hedrick HL„ Liechty K, et al. Cystic adenomatoid malformation volume ratio predicts outcome in prenatally diagnosed cystic adenomatoid malformation of the lung. J Pediatr Surg 2002; 37: 331–8 [22] Bush A, Hogg J, Chitty LS. Cystic lung lesions – prenatal diagnosis and management. Prenat Diagn. 2008; 28: 604–11. [23] Tran H, Fink MA, Crameri J, Cullinane F. Congenital cystic adenomatoid malformation: monitoring the antenatal and short-term neonatal outcome. Aust N Z J Obstet Gynaecol. 2008; 48: 462–6. [24] Schott S, Mackensen-Haen S, Wallwiener M, Meyberg-Solomayer G, Kagan KO. Cystic adenomatoid malformation of the lung causing hydrops fetalis: case report and review of the literature. Arch Gynecol Obstet. 2009; 280: 293–6. [25] Adzick NS, Harrison MR, Cromblehome TH, et al. Fetal lung lesions: management and outcome. Am J Obstet Gynecol 1998; 179: 884–9. [26] Grethel FJ, Wagner AJ, Clifton MS, et al. Fetal intervention for mass lesions and hydrops improves outcome: a 15-year experience. J Pediatr Surg 2007; 42: 117–23.
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[27] Diamond IR, Wales PW, Smith A. Survival after CCAM associated with ascites: a report of a case and review of the literature. J Pediatr Surg 2003; 38: EL-3. [28] Adzick NS, Harrison MR, Flake AW, et al. Fetal surgery for cystic adenomatoid malformations of the lung. J Pediatr Surg 1993; 28: 806–12. [29] Creasy R. Mirror syndromes. In: Goodlin RC (Ed). Care of the fetus. Masson, New York, 1979, pp48–55. [30] Bianchi DW, Cromblehome TM, D’Alton ME. Cystic adenomatoid malformation. In: Bianchi DW, Cromblehome TM, D’Alton ME. Fetology: diagnosis and management of the fetal patient. McGraw-Hill, New York, chap 37. [31] Tsao K, Hawgood S, Vu L, Hirose S, Sydorak R, Albanese CT, Farmer DL, Harrison MR, Lee H. Resolution of hydrops fetalis in congenital cystic adenomatoid malformation after prenatal steroid therapy. J Pediatr Surg 2003; 38: 508–10. [32] Peranteau WH, Wilson RD, Liechty KW, Johnson MP, Bebbington MW, Hedrick HL, Flake AW, Adzick NS. Effect of maternal betamethasone administration on prenatal congenital cystic adenomatoid malformation growth and fetal survival. Fetal Diagn Ther 2007; 22: 365–71. [33] Morris LM, Lim FY, Livingston JC, Polzin WJ, Crombleholme TM. Highrisk fetal congenital pulmonary airway malformations have a variable response to steroids. J Pediatr Surg. 2009; 44: 60–5. [34] Brown RN. Multiple steroid courses result in tumour shrinkage in congenital pulmonary airway malformation (congenital cystic adenomatoid malformation). Prenat Diagn. 2009; 29: 989–91. [35] Leung WC, Ngai C, Lam TP, Chan KL, Lao TT, Tang MH. Unexpected intrauterine death following resolution of hydrops fetalis after betamethasone treatment in a fetus with a large cystic adenomatoid malformation of the lung. Ultrasound Obstet Gynecol. 2005; 25: 610–2. [36] Merchant AM, Peranteau W, Wilson RD, Johnson MP, Bebbington MW, Hedrick HL, Flake AW, Adzick NS. Postnatal chest wall deformities after fetal thoracoamniotic shunting for congenital cystic adenomatoid malformation. Fetal Diagn Ther. 2007; 22: 435–9. [37] Knox EM, Kilby MD, Martin WL, Khan KS. In-utero pulmonary drainage in the management of primary hydrothorax and congenital cystic lung lesion: a systematic review. Ultrasound Obstet Gynecol. 2006; 28: 726–34. [38] Wilson RD, Hedrick HL, Liechty KW, et al. Cystic adenomatoid malformation of the lung: review of genetics, prenatal diagnosis, and in utero treatment. Am J Med Genet A 2006; 140: 151–5. [39] Bermudez ´ C, Perez-Wulff ´ J, Arcadipane M, Bufalino G, Gomez ´ L, Flores L, Sosa C, Bornick PW, Kontopoulos E, Quintero RA. Percutaneous fetal sclerotherapy for congenital cystic adenomatoid malformation of the lung. Fetal Diagn Ther. 2008; 24: 237–40; 31. [40] Lee BS, Kim JT, Kim EA, Kim KS, Pi SY, Sung KB, Yoon CH, Goo HW. Neonatal pulmonary sequestration: clinical experience with transumbilical arterial embolization. Pediatr Pulmonol. 2008; 43: 404–13. [41] Hedrick HL, Flake AW, Crombleholme TM, Howell LJ, Johnson MP, Wilson RD, Adzick NS. The ex utero intrapartum therapy procedure for high-risk fetal lung lesions. J Pediatr Surg. 2005; 40: 1038–43. [42] Lee BS, Kim JT, Kim EA-R, et al. Neonatal pulmonary sequestration: clinical experience with transumbilical arterial embolization. Pediatr Pulmonol 2008; 43: 404–13. [43] Parikh D, Samuel M. Pulmonary stabilisation followed by delayed surgery results in favourable outcome in congenital cystic lung lesions with pulmonary hypertension. Eur J Cardiothorac Surg. 2005; 28: 607–10. [44] Conforti A, Aloi I, Trucchi A, Morini F, Nahom A, Inserra A, Bagolan P. Asymptomatic congenital cystic adenomatoid malformation of the lung: is it time to operate? J Thorac Cardiovasc Surg. 2009 2009 Oct;138(4):826–30. [45] Rothenberg SS. First decade’s experience with thoracoscopic lobectomy in infants and children. J Pediatr Surg. 2008; 43: 40–4. [46] Vu LT, Farmer DL, Nobuhara KK, Miniati D, Lee H. J Thoracoscopic versus open resection for congenital cystic adenomatoid malformations of the lung. Pediatr Surg 2008; 43: 35–39. [47] Kim HK, Choi YS, Kim K, Shim YM, Ku GW, Ahn KM, Lee SI, Kim J. Treatment of congenital cystic adenomatoid malformation: should lobectomy always be performed? Ann Thorac Surg. 2008; 86: 249–53.
[48] Calvert JK, Lakhoo K. Antenatally suspected congenital cystic adenomatoid malformation of the lung: postnatal investigation and timing of surgery. J Pediatr Surg. 2007; 42: 411–4. [49] Papagiannopoulos K, Hughes S, Nicholson AG, Goldstraw P. Cystic lung lesions in the pediatric and adult population: surgical experience at the Brompton Hospital. Ann. Thorac. Surg. 2002; 73:1594–1598. [50] Wong A, Vieten D, Singh S, Harvey JG, Holland AJ. Long-term outcome of asymptomatic patients with congenital cystic adenomatoid malformations. Pediatr Surg Int. 2009; 25: 479–85. [51] Belcher E, Lawson MH, Nicholson AG, Davison A, Goldstraw P. Congenital cystic adenomatoid malformation presenting as in-flight systemic air embolisation. Eur Respir J. 2007; 30: 801–4. [52] Pelizzo G, Barbi E, Codrich D, Lembo MA, Zennaro F, Bussani R, Schleef J. Chronic inflammation in congenital cystic adenomatoid malformations. An underestimated risk factor? J Pediatr Surg. 2009; 44: 616–9. [53] Butterworth SA, Blair GK. Postnatal spontaneous resolution of congenital cystic adenomatoid malformations. J Pediatr Surg 2005; 40: 832–4. [54] Azizkhan RG, Crombleholme TM. Congenital cystic lung disease: contemporary antenatal and postnatal management. Pediatr Surg Int 2008; 24: 643–57. [55] Sueyoshi R, Okazaki T, Uroshihara N, et al. Managing prenatally diagnosed asymptomatic congenital cystic adenomatoid malformation. Pediatr Surg Int 2008; 24: 1111–5. [56] Tsai AY, Liechty KW, Hedrick HL, et al. Outcomes after postnatal resection of prenatally diagnosed asymptomatic cystic lung lesions. J Pediatr Surg 2008; 43: 513–7. [57] Chetcuti PA, Crabbe DC. CAM lungs: the conservative approach. Arch Dis Child Fetal Neonatal Ed. 2006; 91: F463–4. [58] Lo AY, Jones S. Lack of consensus among Canadian pediatric surgeons regarding the management of congenital cystic adenomatoid malformation of the lung. J Pediatr Surg. 2008; 43: 797–9. [59] Nur S, Badr R, Sandoval C, Brudniki A, Yeh A. Syndromic presentation of a pleuropulmonary blastoma associated with congenital cystic adenomatoid malformation. A case report. J Pediatr Surg. 2007; 42: 1772–5. [60] Ramos SG, Barbosa GH, Tavora FR, Jeudy J, Torres LA, Tone LG, Trad CS. Bronchioloalveolar carcinoma arising in a congenital pulmonary airway malformation in a child: case report with an update of this association. J Pediatr Surg. 2007; 42: E1–4. [61] West D, Nicholson AG, Colquhoun I, Pollock J. Bronchioloalveolar carcinoma in congenital cystic adenomatoid malformation of lung. Ann Thorac Surg. 2007; 83: 687–9. [62] MacSweeney F, Papagiannopoulos K, Goldstraw P, Sheppard MN, Corrin B, Nicholson AG. An assessment of the expanded classification of congenital cystic adenomatoid malformations and their relationship to malignant transformation. Am J Surg Pathol. 2003; 27: 1139–46. [63] Federici S, Domenichelli V, Tani G, Sciutti R, Burnelli R, Zanetti G, Domini ` R. Pleuropulmonary blastoma in congenital cystic adenomatoid malformation: report of a case. Eur J Pediatr Surg. 2001; 11: 196–9. [64] de Perrot M, Pache JC, Spiliopoulos A. Carcinoma arising in congenital lung cysts. Thorac Cardiovasc Surg. 2001; 49: 84–5. [65] Indolfi P, Casale F, Carli M, Bisogno G, Ninfo V, Cecchetto G, Bagnulo S, Santoro N, Giuliano M, Di Tullio MT. Pleuropulmonary blastoma: management and prognosis of 11 cases. Cancer. 2000; 89: 1396–401. [66] Granata C, Gambini C, Balducci T, Toma P, Michelazzi A, Conte M, Jasonni V. Bronchioloalveolar carcinoma arising in congenital cystic adenomatoid malformation in a child: a case report and review on malignancies originating in congenital cystic adenomatoid malformation. Pediatr Pulmonol. 1998; 25: 62–6. [67] d’Agostino S, Bonoldi E, Dante S, Meli S, Cappellari F, Musi L. Embryonal rhabdomyosarcoma of the lung arising in cystic adenomatoid malformation: case report and review of the literature. J Pediatr Surg. 1997; 32: 1381–3. [68] Ribet ME, Copin MC, Soots JG, Gosselin BH. Bronchioloalveolar carcinoma and congenital cystic adenomatoid malformation. Ann Thorac Surg.; 60: 1126–8. [69] Benjamin DR, Cahill JL. Bronchioloalveolar carcinoma of the lung and congenital cystic adenomatoid malformation. Am J Clin Pathol. 1991; 95: 889–92. [70] Sheffield EA, Addis BJ, Corrin B, McCabe MM. Epithelial hyperplasia and malignant change in congenital lung cysts. J Clin Pathol. 1987; 40: 612–4.
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[71] Ueda K, Gruppo R, Unger F, Martin L, Bove K. Rhabdomyosarcoma of lung arising in congenital cystic adenomatoid malformation. Cancer. 1977; 40: 383–8. [72] Papagiannopoulos KA, Sheppard M, Bush A, Goldstraw P. Pleuropulmonary blastoma: is prophylactic resection of congenital lung cysts effective? Ann Thorac Surg 2001; 72: 604–605. [73] Vargas SO, Korpershoek E, Kozakewich HP, de Krijger RR, Fletcher JA, Perez-Atayde AR. Cytogenetic and p53 profiles in congenital cystic adenomatoid malformation: insights into its relationship with pleuropulmonary blastoma. Pediatr Dev Pathol. 2006; 9: 190–5. [74] Nur S, Badr R, Sandoval C, Brudniki A, Yeh A. Syndromic presentation of a pleuropulmonary blastoma associated with congenital cystic adenomatoid malformation. A case report. J Pediatr Surg 2007; 42: 1772–5. [75] Hill DA, Jarzembowski JA, Ppriest JR, Williams G, Schoettler P, Dehner LP. Type 1 pleuropulmonary blastoma: pathology and biology study of 51 cases from the international pleuropulmonary blastoma registry. Am J Surg Pathol 2008; 32: 282–95. [76] Fumino S, Iwai N, Kimura O, Ono S, Higuchi K. Preoperative evaluation of the aberrant artery in intralobar pulmonary sequestration using multidetector computed tomography angiography. J Pediatr Surg. 2007; 42: 1776–9. [77] Aite L, Zaccara A, Trucchi A, Brizzi C, Nahom A, Iacobelli B, Capolupo I, Bagolan P. J Perinat Med. 2009 Jun 3. Epub ahead of print [78] Larroquet M. Congenital cystic adenomatoid malformation (CCAM)does prenatal ultrasonography modified surgical indications? Saudi Med J 2003; 24: 34–9. [79] Komori K, Kamagata S, Hirobe S, Toma M, Okumura K, Muto M, Kasai S, Hayashi A, Suenaga M, Miyakawa T. Radionuclide imaging study of longterm pulmonary function after lobectomy in children with congenital cystic lung disease. J Pediatr Surg. 2009; 44: 2096–100. [80] Sauvat F, Michel JL, Benachi A, Emond S, Revillon Y. Management of asymptomatic neonatal cystic adenomatoid malformations. J Pediatr Surg. 2003; 38: 548–52.
O.4.3 New therapies for chest wall and spine disorders in children G.J. Redding1,2 . 1 Pediatrics, University of Washington School of Medicine; 2 Pulmonary and Sleep Medicine Division, Seattle Children’s Hospital, Seattle, Washington, USA Correspondence: J. Redding. Pulmonary and Sleep Medicine Division, Office A-5937, Seattle Children’s Hospital, 4800 Sand Point Way N.E., Seattle, Washington, USA. Telephone: 206 987 2174; fax: 206 987 2639. E-mail: [email protected] Keywords: Scoliosis, thoracic insufficiency children
Traditionally chest wall or thoracic cage disorders were considered independently from spine disorders. In many cases this is appropriate, such as with pectus deformities. However, there is an increasing awareness that thoracic and pulmonary disorders can affect spine growth and configuration and that spine deformities affect thoracic cage, diaphragm, and hence respiratory growth and function. Recently, the term Thoracic Insufficiency Syndrome has been coined to describe a variety of spine and thoracic cage disorders that produce “an inability to support normal respiratory function and postnatal lung growth in children with skeletal immaturity [1]. TIS results from structural abnormalities of bones in the spine and ribs, known as primary TIS or it can occur as a result of scoliosis due to neuromuscular conditions producing weakness or spasticity (secondary TIS). A third category of TIS are thoracic deformities that occur as a result of surgical resection or congenital absence of ribs, producing a flail chest syndrome. Changes in spine configuration that contribute to poor chest wall excursion and loss of thoracic cage compliance include scoliosis, kyphosis, and lordosis of the thoracic region with or without a cervical or lumbar component. The deformities can vary by site and length along the spine and can be associated with primary rib anomalies, such as fused ribs. Congenital scoliosis includes conditions that have structural anomalies of the vertebrae, such as hemi-vertebrae and unsegmented or block vertebrae. Infantile idiopathic scoliosis can be equally severe but has normal
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vertebral anatomy and rib anatomy. In both conditions, the spine can deform progressively over time, producing progressive restrictive lung disease. Importantly, any one of these structural features, including the often-used Cobb angle, correlates poorly with functional respiratory measurements [2,3]. Another type of thoracic cage deformity in primary TIS includes disorders that produce a small chest wall. Jeune’s syndrome is the classic example of circumferential thoracic hypoplasia with a loss of intrathroacic volume for the lung. There are cases of Jeune’s syndrome that have survived after infancy, suggesting a continuum of severity exists. A small thorax also occurs in spondylocostal dysplasia and spondylothoracic dysplasia, previously known together as Jarcho-Levin syndrome. This is a disease of deformed and fewer vertebrae and ribs, sometimes fused, and hence a shortened thoracic cage in the cephalad-caudad dimension. Mortality is greater with spondylothoracic dysplasia which also produces a scoliosis. The physiologic consequences of TIS include loss of vital capacity due to small intrathoracic space and also loss of chest wall mobility. Lung functions performed under anesthesia have documented severely reduced total pulmonary compliance (lungs and chest wall combined) with TIS [4]. Scoliosis also produces a progressive rotational deformity of the spine with rotation of the ribs producing a thoracic twist. This rotation leads to deformation of intrathoracic contents with a “windswept” look on transverse images of computerized thoracic tomographic (CT) scans. The result is development of asymmetry in right and left lung volumes and right and left lung ventilation and perfusion, as documented by ventilation and perfusion scans [2]. In addition to the reduced and asymmetric lung volumes, there is evidence of reduced diaphragmatic excursion by dynamic Magnetic Resonance imaging (MRI) and reduced respiratory muscle force generation due to abnormal configuration rather than primary muscle weakness per se. Associated problems related to these functional limitations include poor weight gain, poor sleep quality, and poor quality of life [5]. More than 50% of children with primary TIS have body mass indices (using arm span instead of height) of <5%. Children with TIS are also predisposed to sleep-related hypopneas (but not apneas) with recurrent hypoxemia during sleep and an increased arousal index [3]. This may also contribute to poor weight gain. The quality of life of children with TIS is worse than among children with asthma arthritis, and children awaiting heart transplantation [5]. Physical disability and burden of family care are the domains of the quality of life survey tools that are most affected by TIS. Late events can include pulmonary hypertension and cor pulmonale. Approximately 10% of the 320 children who underwent surgical therapy with the vertical expandible titanium prosthetic rib (VEPTR) were ventilator-dependent when first assessed for surgical therapy. Where once the outcome of these children was considered poor if the chest wall were small or the spine deformity progressed, the advent of new surgical spine and thoracic devices has transformed this population of children into a new group with chronic restrictive non-progressive respiratory disease. There are few studies of natural history of TIS conditions reported in the literature. The most quoted study is by Pehrsson et al using a national health database to determine mortality in high risk subgroups of adults with scoliosis [6]. The data is complicated by inclusion of neuromuscular weakness syndromes (including poliomyelitis) in addition to primary spinal structural deformities. With this caveat, the authors found that mortality due to early onset scoliosis (beginning at <8 years of age) increased beginning at 40 years of age and worsened thereafter. The concept put forth is that lung growth never reached normal values when postnatal growth of the lung and thorax were complete and that subsequent changes in lung function due to aging then impacted these people with diminished pulmonary reserve due to underlying restrictive pulmonary changes.
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[27] Teper AM, Marcos CY, Theiler G, Colom AJ, Fainboim L. Association between HLA and the incidence of bronchiolitis obliterans (BO) in Argentina. Am J Respir Crit Care Med 2004; 169: 382 (Abstract). [28] Teper A, Colom A, Bailliet G, Martnez-Marignac V, Bianchi N. Association between the incidence of bronchiolitis obliterans (BO) in Argentine children and their native-american maternal and paternal lineage. Am J Respir Crit Care Med 2003; 167: 998. (Abstract.) [29] Kajon A, Gigliotti A, Harrod K. Acute inflammatory response and remodeling of airway epithelium after subspecies B1 human adenovirus infection of the mouse lower respiratory tract. J Med Virol 2003; 71: 233–244. [30] Leong MA, Nachajon R, Ruchelli E et al. Bronchitis obliterans due to Mycoplasma pneumonia. Pediatr Pulmonol 1997; 23; 375–338. [31] Massie R, Armstrong D. Bronchiectasis and bronchiolitis obliterans post respiratory syncytial virus infection: think again. J Paediatr Child Health 1999; 35: 497–498. [32] Hirschheimer M, Silva P, Giudici R et al. Simultaneous viral infection and childhood bronchiolitis obliterans. Braz J Infect Dis 2002; 6: 146– 148. [33] Swyer PR, James GCW. A case of unilateral pulmonary emphysema. Thorax 1953; 8: 133–136. [34] MacLeod VVM. Abnormal transradiancy of one lung. Thorax 1954; 9: 147–153. [35] Leung A, Fisher K,Valentine V, Girgis R, Berry G, Robbins R, Theodore J. Bronchiolitis obliterans after lung transplantation, detection using expiratory HRCT. Chest 1998; 113: 365–370. [36] Teper AM, Kofman CD, Maffey AF et al. Lung function in infants with chronic pulmonary disease after severe adenoviral illness. J Pediatr 1999; 134: 730–733. [37] Maffey A, Colom A, Kofman C, Vidaurreta S, Teper A. Longitudinal study of pulmonary function in infants with post viral chronic pulmonary disease (PCPD). Am J Respir Crit Care Med 1996; 153: 498. (Abstract.) [38] Colom AJ, Maffey A, Navarra F, Teper A. Pulmonary function in children with post-viral chronic pulmonary disease (PCPD). Am J Respir Crit Care Med 2002; 163: A159. (Abstract.) [39] Colom AJ, Navarra F, Kofman C, Teper A. Respiratory mechanics in children with post-viral chronic pulmonary disease (PCPD). Am J Respir Crit Care Med 2002; 163: A159. (Abstract). [40] Kim CK, Kim SW, Kim JS et al. Bronchiolitis obliterans in the 1990s in Korea and the United States. Chest 2001; 120: 1101–1106. [41] Fullmer J, Fan L, Dishop M, Rodgers C, Krance R. Successful treatment of bronchiolitis obliterans in a bone marrow transplant patient with tumor necrosis factor-a blockade. Pediatrics 2005; 116: 767–770. [42] Gerhardt S, McDyer J, Girgis R, Conte J, Yang S, Orens J. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome. Results of a pilot study. Am J Respir Crit Care Med 2003; 168: 121–125. [43] Colom A and Teper AM. Clinical prediction rule to diagnose postinfectious bronchiolitis obliterans in children. Pediatr Pulmonol 2009; 44:1065–1069.
General Topics Lung Development and Related Respiratory Pathologies 10:20–11:50
Room C
O.4.1 Advances in lung development A.A. Hislop. Institute for Child Health, UCL, 30 Guilford St, London WC1N 1EH, United Kingdom Correspondence: #447 (0)207 905 2337, #44 (0)207 813 8459. E-mail: [email protected]
The description of the developing lung is well known. The primary goal is to produce a large gas exchange area within a relatively small volume of thorax. It appears in the 4th week of gestation and by a process of branching morphogenesis the entire bronchial tree is present by the 16th week of gestation. Alveoli are first formed in the last 10 weeks of gestation and they continue to form for at least 2–3 years after birth. Blood vessels appear alongside the airways and alveoli as they form by vasculogenesis and angiogenesis. Many influences in utero and childhood will lead to a restriction of normal growth and it is accepted that reduced lung function at birth and
in early childhood tracks into adulthood. Studies on the control of normal and abnormal growth should give us clues as to how we may repair abnormal lungs and it is this field that is showing the most advances at the moment. Throughout lung development there is interaction of many growth factors and transcriptional factors. In addition to these genetic influences there are the physical effects of space, fluid, nutrition and environment which includes oxygen tensions and maternal smoking. Since airway development is complete early in gestation it is unlikely that any abnormalities in airway numbers can be reversed. However alveolar development continues postnatally and it is the encouragement of new alveolar growth which is studies most using experimental models. Post pneumonectomy or lobectomy there is increase in lung volume of the residual lung to fill space. This can be a very rapid response. In adult dogs HIF-1a and vascular endothelial growth factor are increased after only 3 days. Both of these are known to promote angiogenesis and alveolar formation. Maternal food restriction and deficiency of Vitamin A and D lead to abnormal lungs in man and other species. In experimental animals supplemental feedings can restore alveolar growth again very rapidly. Repair in the airways is largely due to the basal cells of the epithelium while in the alveolar region it is the Type II alveolar cells. However there are also bronchioalveolar stem cells and a pluripotent side population of cells derived from the bone marrow. Circulating endothelial progenitor cells can also promote capillary formation. The combination of these can lead in animals to formation a new alveoli. Reference(s) Baraldi E, Filippone M, N Engl J Med 2007: 357, 1946–55 Van Haaften T, Thebaud B, Pediatr Res 2006: 59, 94R-99R
O.4.2 Controversies in the management of cystic lung disease A. Bush1,2 . 1 Paediatric Respirology, Imperial School of Medicine at National Heart and Lung Institute; and 2 Royal Brompton Hospital, UK Correspondence: A. Bush. Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Tel: 207 351 8232; fax: 207 351 8763. E-mail: [email protected] Keywords: Sequestration, bronchogenic cyst, congenital cystic adenomatoid malformation, fetal surgery, hydrops, sarcoma, pleuropulmonary blastoma
Abstract: The antenatal diagnosis of a congenital thoracic malformation (CTM) leads to anxiety and uncertainty as to best management. CTM comprises congenital cystic adenomatoid malformation, sequestration, congenital lobar emphysema, enteric and bronchogenic cysts, and bronchial atresia. Most require only observation antenatally, and reduce in size substantially in the third trimester. If fetal hydrops develops, then antenatal intervention, usually surgical, is required, because untreated mortality is high. If the baby is symptomatic in the newborn period, then surgical intervention is clearly needed. The treatment of the asymptomatic baby is the major controversial area. Advocates of early surgery point to the complications of CTM, which include infection, pneumothorax, bleeding and malignant transformation. The proponents of conservative management retort that some CTMs disappear postnatally, and that the complication rate is unknown; many children appear never to need surgery. Furthermore, excision of a CTM does not totally eliminate the risk of a subsequent malignancy. Counselling of the family on a case by case basis is needed, both antenatally and postnanatally, stressing the limitations of present evidence. Introduction: There is not enough evidence to give definite opinions to parents of a foetus in whom a congenital thoracic malformation (CTM) has been discovered. We do know that: 1. Many antenatally diagnosed CTMs will regress spontaneously before birth. Thus any fetal intervention runs the risk of being unnecessary and meddlesome. Rare cases of true spontaneous postnatal regression of a CTM have been recorded [1].
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2. If the child is significantly symptomatic in the newborn period despite medical management, then surgery is indicated. However, an asymptomatic infant who is offered surgery will be being exposed to a small risk of iatrogenic complications. 3. There are late complications of CTMs, including infection, pneumothorax, malignant transformation, high output cardiac failure and air embolism, but the risk is unkown. Malignant transformation is not always preventable by resection. This review focuses briefly on the ante- and post-natal nomenclature to use in discussions, the antenatal presentations of CTMs, and the ante- and post-natal options with their advantages and disadvantages, concluding with a suggested practical approach to parents. These may be contrasted with other recent reviews [2,3]. Amongst the problems of making sense of the literature are the diversity of the histological patterns, and the rarity of the lesions, estimated at between 1 in 20–30,000 live births [4]. Later post-natal presentations of CTMs, and a detailed account of their pathology, are discussed in detail elsewhere [5]. Nomenclature of CTMs: The nomenclature of congenital lung disease has been confusing for the following reasons. 1. Sequestration and cystic adenomatoid malformation (CCAM) are often assumed to be separate identities, and pathologically have distinct features, but histological features of both may be found within the same lesion (‘Hybrid lesions’). 2. There is inconsistent use of nomenclature before and after birth. For example, the term CCAM is used by perinatologists to describe a lesion that may well disappear before birth, but is used postnatally to describe an abnormality which often but not invariably requires lobectomy. 3. No matter how sophisticated the imaging modality used, the clinician can only see shades of grey, and should not make unwarranted pathological assumptions from these pictures. The same clinical appearance (e.g., a multicystic mass) may have one of several different histological appearances when excised. 4. The pathologist who can examine the excised lesion, and can provide a precise account of what it contains, quite different from the clinician. It is suggested that the following principles should be followed when looking at clinical images, either antenatally or postnatally [6]: a. What is actually seen should be described, without embryological or pathological speculation, which may later be proved wrong. A simple ‘catch-all’ term, congenital thoracic malformation (CTM) has been proposed to replace the old nomenclature in clinical discussions [6], because this makes no pathological assumptions. The spectrum of CTM includes CCAM, sequestration, bronchogenic and foregut cysts, and bronchial atresia with distal cystic degeneration [7]. Postnatally at least, a congenital large hyperlucent lobe (CLHL, “congenital lobar emphysema” is separated off, because late complications are almost unknown; antenatally, CLHL may be impossible to distinguish from other pathological causes of CTM b. The description should be in simple clear language. Thus a CTM could described (antenatally or postnatally) as solid or cystic; if cystic, the cysts should be described as single or multiple, whether large or small (ideally with the size measured rather than estimated), thin or thick walled, and whether the contents are purely fluid or (postnatally) they contain air should also be noted. Speculating about pathology from antenatal ultrasound scans often leads to a revision of the diagnosis once the lesion has been resected [8] c. The rest of the respiratory system should be described in a systematic manner as far as possible, in particular the arterial and venous trees. d. Other organs should be considered systematically, because associated lesions will be missed unless carefully sought. Antenatal presentations of CTMs: Most abnormalities are detected around 20 weeks’ gestation, at the routine fetal anomaly scan,
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either from an abnormality of amniotic fluid volume or the discovery of a mass. CTMs can cause polyhydramnios in isolation as a result of compression of the fetal esophagus preventing the swallowing of amniotic fluid, or as part of fetal hydrops. A mass (cystic or solid) may be directly identified in the fetal thorax or its presence may be suspected because of mediastinal shift. Increasingly, fetal MRI is being used further to image suspected lesions and the surrounding lung [9–13]. MRI can confirm the presence of the mass, delineate the blood supply, and help to assess the residual lung parenchyma [9,10], although the place of this technique remains to be determined. Cystic CTMs usually occur alone, although other associated abnormalities have been described, including bronchopulmonary sequestration, congenital diaphragmatic hernia and extrapulmonary malformations including renal and cardiac anomalies, but not aneuploidy [14,15]. A so-called fetal sequestrated lobe is most often identified as an echogenic mass of uncertain origin in the chest or sub-diaphragmatic area; demonstration of an aortic blood supply, usually by colour flow Doppler, is not diagnostic, because a CCAM may also have an aortic blood supply (above). The results of investigation may result in fetal therapy being offered (below), or more usually, identifies fetuses that should be delivered in a centre offering high level neonatal intensive care where early postnatal surgery can be performed if needed. Where any lesion has persisted or increased in size and mediastinal shift persists in the third trimester, delivery in such a centre is advisable. Options for antenatal management of CTMs: a paediatric perspective: The first big question is, is any antenatal intervention warranted at all? The prognosis for a fetus with a cystic CTM (“CCAM”) is generally good; the lesion tends to peak in size at 25 weeks, and then regress [16]. One series of 48 CTMs [17] reported that in 22 cases, the lesions disappeared, and only 6 became severe. Another group reported that 64 of 67 fetuses with an antenatally diagnosed CTM were born alive, of whom 42 underwent postnatal surgery [18]. Accurate prediction of outcome can be difficult on a single scan, and serial scans should be undertaken to detect lesions which are not regressing. Antenatal ultrasound features which were predictive of hydrops were MTR (ratio of mass size to thorax size), cystic predominance, and diaphragmatic eversion; these fetuses need particularly careful follow-up [19]. Protocols for ultrasound follow-up have been described [20]. MRI can be used to calculate CTM volume to head ratio (CVR) [21]; a ration of ≥1.6 is 80% predictive of progression to hydrops, whereas CVR ≤1.6 had a good prognosis (only 2% becoming hydropic). CTMs with a single dominant cyst may behave unpredictably, and MRI should be interpreted with caution in this context. However, all the series to 2007, which were summarised in [22], and additional series published since then [2,20,23] have confirmed the key message, that only a tiny minority of antenatally diagnosed CTMs will require antenatal intervention. However, equally clear is that if the fetus becomes hydropic, mortality without intervention is close to 100% [24], but this can be improved by a number of interventions [25,26]. It should be noted that there are rare but well documented cases of CTMs causing hydrops which have resolved spontaneously [27]. A very rare complication is ‘maternal mirror syndrome’ [28–30], in which rapid development of pre-eclampsia, proteinuria and pulmonary oedema herald maternal death unless fetus and placenta are urgently delivered. If intervention is needed, the options which have been proposed include cyst decompression or pleuro-amniotic shunting for in particular isolated pleural effusion, intra-uterine surgery or sclerotherapy, embolization of collateral vessels, radiofrequency ablation, and maternal steroid therapy. For the most part, experience is limited to small case series, and there are no controlled clinical trials. There are anecdotal reports of the use of maternal injections of betamethasone in fetal CTM with better outlook than historical controls [31,32]. Around 50% of hydropic fetuses may respond to maternal betamethasone [33]. However, an unexpected
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intra-uterine death has been reported after resolution of hydrops following betamethasone therapy [34]. Furthermore, the response is very variable, and, if the CTM progresses despite a first course of steroids, then further courses are not useful, and surgical management is required [33], although this is disputed [34]; clearly more data are needed. There are many surgical options. Where there are single or multiple large cysts with associated hydrops or polyhydramnios improvement has been reported with in-utero decompression by thoracocentesis or the insertion of a pleuroamniotic shunt [20,36,37]. Shunting is only beneficial in the setting of antenatal CTM when there is pleural effusion or fetal hydrops [37]. The prognosis for shunted CTMs containing a dominant large cyst is good, even if there is hydrops, with around 75% survival [38]. It may be complicated by later chest deformity, particularly if shunting is performed at less than 21 weeks gestation [36]. This contrasts with the results of fetal surgery, also occasionally used in these lesions [20], where the incision heals in utero without leaving a scar. Other techniques reported in small series include sclerotherapy of abnormal feeding vessels, and sclerotherapy of the mass under ultrasound control [39,40]. If the feeding vessel is occluded by fetal sclerotherapy, around half the fetuses will need no further postnatal treatment [2]. A case in which radiofrequency ablation was used [19] to ablate a large CTM resulted in fetal death, presumed to be due to hemorrhage into the necrotic mass. This case would suggest cautious use of any procedure, either ante- or post-natal, which results in infarction of the mass. Options for postnatal management of CTMs: a paediatric perspective: At the most dramatic end of the spectrum, a fetus with a huge malformation severely compromising the airway will require ex-utero, intrapartum treatment (EXIT procedure) [41]. Similarly, the baby who is symptomatic with a large CTM or CLHL will require treatment in the neonatal period; very occasional big malformations require EXIT to resection on placental support [41]. If less severely affected babies nonetheless remain too tachypnoeic to feed, or are severely stridulous because the airway is compressed by the CTM, or are less severely tachypnoeic but fail to thrive, then surgical treatment is inevitable. For many abnormalities, surgery is the best and definitive treatment; occasionally a lesser procedure such as embolization of a feeding vessel may be all that is needed [42]. If pulmonary hypertension complicates a CTM, then stabilization prior to surgery is preferable [43]. Symptomatic babies undergoing surgery in the newborn period have a higher complication rate than asymptomatic infants [44]. For all but the smallest, sickest infants, lobectomy is a safe and well tolerated procedure, with few if any significant sequelae. Increasingly, this is performed thoracoscopically; the inpatient stay and duration of placement of chest drains is shorter [45]; however preceding pneumonia may mandate conversion of thoracoscopy to formal thoracotomy [46], which is a consideration when deciding whether to defer surgery in the asymptomatic child (below). The minimal possible resection should be performed [47]. However, pneumonectomy carries a significant mortality in infancy. There is also considerable long term morbidity, in particular scoliosis which may worsen dramatically during the pubertal growth spurt. What to do for the baby who is well and thriving, but who has been given an antenatal diagnosis of a CTM, is completely unclear. They should have a CXR prior to discharge. In many it will be normal, but subsequent, more detailed imaging may reveal malformations; CXR was only 61% sensitive for malformations, compared with the gold standard of HRCT [48]. There were no false positive diagnoses on HRCT. However the unanswerable and related questions that arise are (1) what further imaging should be performed; and (2) should such infants be submitted to surgery, and if so, when? The question of surgery has to be dealt with first, because clearly here is little point in requesting a HRCT in a very young child if no action will be taken on the results. Surgery for asymptomatic CTMs is a really controversial area. If the lesion is cystic, then it is likely (but unproven) that infection
will occur sooner or later, and some would advise prophylactic excision [49]. It is said that all lesions should be excised to prevent malignant transformation, but there definitive evidence against this view (below). Other rare complications, which would definitely be prevented by surgery include bleeding into or from the cysts, pneumothorax, and air embolism [50–54]. Whether an asymptomatic malformation should be resected to facilitate normal lung growth is not clear. The advocates of an aggressive approach argue that an asymptomatic CTM merits surgery because it is likely that there will be a complicating infection of the cyst eventually, which may make the operation more difficult, sometimes mandating conversion of VATS to a thoracotomy [46,49]. Furthermore, in one series, 50% of CTMs resected after the age of six months were thought to show evidence of chronic infection [48], a higher prevalence than I have seen in my practice. Anecdotally, I have seen a single child who was thought to be asymptomatic, and had a large CTM removed which on histology showed evidence of chronic infection. Post-operatively, the child was much happier and healthier than before, and the parents realized that in fact the child had been a lot less well prior to surgery than they had thought. However, this has been the exception in my experience. Another challenging observation is that there is evidence of chronic inflammation even in most CTMs, even those which were resected very early in life [52]. Again, the practical significance of this is hard to determine. Finally, in one very small series (as with all others, uncontrolled) those initially treated conservatively, and then subsequently undergoing surgery had a longer operation time and greater blood loss, but were not otherwise disadvantaged [55]. Surgery is generally uncomplicated [56]. In favor of conservative management is the fact that some lesions may regress completely post-natally [1,53]. Furthermore, data presented briefly in a letter to the Editor suggested that in more than 100 malformations, 10% required surgery in the newborn period, a further 5% became infected and subsequently had an operation, and 85% remained symptom free with no surgery; the detailed duration of follow-up is not stated [576]. Others report a much higher proportion of children requiring surgery [50,51], many as an emergency. These children tended to need larger resections, although whether this was because of emergency presentation is not clear. A Canadian survey highlighted that even among surgeons there was no consensus about whether to operate on an asymptomatic CTM, what procedure to do and when to do it. Of interest, 80% of CTMs managed conservatively initially eventually underwent surgery; however, it is not clear from the manuscript what proportion became symptomatic, and how many underwent surgery because of peer or parental pressure [58]. If the risk of these lesions becoming infected is unknown, still less do we know the risk of malignant transformation. The following facts are clear. • Primary pulmonary malignancy in childhood is very rare, and the evidence that there is in fact an increased risk in most types of CTM is tenuous [3] • There are case reports and case series of co-existence of CTM and a variety of primary pulmonary malignancies [59– 71]. These include bronchioloalveolar carcinoma and Type 1 CCAM [61,68,71]; pleuropulmonary blastoma (PPB) and Type 4 CCAM [62], and PPB and a congenital lung cyst [65]; CCAM (type unspecified) and rhabdomyosarcoma [66,67]. Further information on the relationship between CCAM and PPB can be found at www.ppbregistry.org. • Even complete removal of a CTM cannot prevent the development of malignant disease elsewhere in the lung [69,72,73], implying that the malformation is merely a marker of increased malignant potential throughout the lungs, in which case removing the malformation would not deal with the underlying problem. Thus although one group [74] suggested on the basis of cytogenetic and p53 profiles that CCAM was not a premalignant condition, the rest of the literature is less reassuring. It is suggested that a higher
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incidence of suspicion is justified in those with bilateral disease, a family history of pleuropulmonary blastoma, pulmonary cysts or renal anomalies, or a close relative with a childhood malignancy, especially Wilm’s tumour or medulloblastoma. The registry data on the relationship of pleuropulmonary blastoma and CTM has been reviewed [75]. Malignant transformation is rare, but more evidence is needed. Thus we do not know the risk of infection or malignant transformation. Surgery prevents infection, although cysts recurrence has been described [50], but it does not always prevent pulmonary malignancy. If surgery is contemplated, it is essential to delineate the anatomy of the CTM, and in particular the blood supply. HRCT scanning after contrast, with modern reconstruction techniques is used to delineate the blood supply and venous drainage CTM [76]. MRI may also be used. What to say to the parents: a practical approach: If a large CTM is discovered at the 20 week anomaly scan, then parental anxiety is likely to be huge; almost paradoxically parents worry more about the uncertainty around a usually benign prognosis CTM than about definitively bad prognosis lesions such as congenital diaphragmatic hernia [77]. Parents should be advised that the vast majority of CTMs require no antenatal intervention, and the likeliest outcome is the safe delivery of a healthy infant, for whom an elective operation may need to be considered at some stage. Early consultation with respiratory paediatricians and paediatric surgeons is helpful. Progress is followed with serial ultrasound scans. Parents of the rare fetus requiring antenatal intervention should receive counselling from a specialist perinatologist. My personal, non-evidence based practice is to recommend postnatal surgery for all but trivial CTMs, so that an elective, low risk procedure can be performed at a convenient time, rather than the possibility of having to deal as an emergency with an infected malformation. If the child is well and thriving, I perform HRCT without contrast in the first few weeks of life; if the CTM has truly involuted, or of trivial size, then no further action is needed. If the size is significant, then timing of surgery is a trade-off between allowing the baby to grow, and not allowing time for complications to develop. Since complications are rare before age 2 years [55] (although definitely described [78]) I advise surgery towards the end of the second year of life. However, there is recent, albeit indirect evidence from post-operative nuclear medicine studies that lung growth postoperatively may be better if surgery is performed before a year of age, in uninfected children [79]. Interestingly, the size of resection was apparently irrelevant. In preparation for surgery, I recommend a second HRCT scan with contrast at 18 months of age; if the mass has involuted, surgery is cancelled. Immediate surgery in the postnatal period may mean some children will undergo an unnecessary operation. It could be argued that the first HRCT is unnecessary, but it allows some infants to be discharged immediately; furthermore, if the CTM is in fact a CLHL (“congenital lobar emphysema”) and the child is asymptomatic, then the family can be reassured that surgery is highly unlikely ever to be necessary, since these lesions do not become infected, and no further imaging is required. In summary, given the lack of evidence, at all stages the paediatrician would do well to share with the parents the little that is known, and the large amount that is unknown, and discuss the lesions with the family on a case by case basis [80]. Reassuringly, whatever options are chosen, the long term outlook for the vast majority is excellent. Reference(s) [1] Nagata K, Masumoto K, Tesiba R, Esumi G, Tsukimori K, Norio W, Taguchi T. Pediatr Surg Int. 2009 Aug 7. [Epub ahead of print.] [2] Cavoretto P, Molina F, Poggi S, Davenport M, Nicolaides KH. Prenatal diagnosis and outcome of echogenic fetal lung lesions. Ultrasound Obstet Gynecol. 2008; 32: 769–83.
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O.4.3 New therapies for chest wall and spine disorders in children G.J. Redding1,2 . 1 Pediatrics, University of Washington School of Medicine; 2 Pulmonary and Sleep Medicine Division, Seattle Children’s Hospital, Seattle, Washington, USA Correspondence: J. Redding. Pulmonary and Sleep Medicine Division, Office A-5937, Seattle Children’s Hospital, 4800 Sand Point Way N.E., Seattle, Washington, USA. Telephone: 206 987 2174; fax: 206 987 2639. E-mail: [email protected] Keywords: Scoliosis, thoracic insufficiency children
Traditionally chest wall or thoracic cage disorders were considered independently from spine disorders. In many cases this is appropriate, such as with pectus deformities. However, there is an increasing awareness that thoracic and pulmonary disorders can affect spine growth and configuration and that spine deformities affect thoracic cage, diaphragm, and hence respiratory growth and function. Recently, the term Thoracic Insufficiency Syndrome has been coined to describe a variety of spine and thoracic cage disorders that produce “an inability to support normal respiratory function and postnatal lung growth in children with skeletal immaturity [1]. TIS results from structural abnormalities of bones in the spine and ribs, known as primary TIS or it can occur as a result of scoliosis due to neuromuscular conditions producing weakness or spasticity (secondary TIS). A third category of TIS are thoracic deformities that occur as a result of surgical resection or congenital absence of ribs, producing a flail chest syndrome. Changes in spine configuration that contribute to poor chest wall excursion and loss of thoracic cage compliance include scoliosis, kyphosis, and lordosis of the thoracic region with or without a cervical or lumbar component. The deformities can vary by site and length along the spine and can be associated with primary rib anomalies, such as fused ribs. Congenital scoliosis includes conditions that have structural anomalies of the vertebrae, such as hemi-vertebrae and unsegmented or block vertebrae. Infantile idiopathic scoliosis can be equally severe but has normal
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vertebral anatomy and rib anatomy. In both conditions, the spine can deform progressively over time, producing progressive restrictive lung disease. Importantly, any one of these structural features, including the often-used Cobb angle, correlates poorly with functional respiratory measurements [2,3]. Another type of thoracic cage deformity in primary TIS includes disorders that produce a small chest wall. Jeune’s syndrome is the classic example of circumferential thoracic hypoplasia with a loss of intrathroacic volume for the lung. There are cases of Jeune’s syndrome that have survived after infancy, suggesting a continuum of severity exists. A small thorax also occurs in spondylocostal dysplasia and spondylothoracic dysplasia, previously known together as Jarcho-Levin syndrome. This is a disease of deformed and fewer vertebrae and ribs, sometimes fused, and hence a shortened thoracic cage in the cephalad-caudad dimension. Mortality is greater with spondylothoracic dysplasia which also produces a scoliosis. The physiologic consequences of TIS include loss of vital capacity due to small intrathoracic space and also loss of chest wall mobility. Lung functions performed under anesthesia have documented severely reduced total pulmonary compliance (lungs and chest wall combined) with TIS [4]. Scoliosis also produces a progressive rotational deformity of the spine with rotation of the ribs producing a thoracic twist. This rotation leads to deformation of intrathoracic contents with a “windswept” look on transverse images of computerized thoracic tomographic (CT) scans. The result is development of asymmetry in right and left lung volumes and right and left lung ventilation and perfusion, as documented by ventilation and perfusion scans [2]. In addition to the reduced and asymmetric lung volumes, there is evidence of reduced diaphragmatic excursion by dynamic Magnetic Resonance imaging (MRI) and reduced respiratory muscle force generation due to abnormal configuration rather than primary muscle weakness per se. Associated problems related to these functional limitations include poor weight gain, poor sleep quality, and poor quality of life [5]. More than 50% of children with primary TIS have body mass indices (using arm span instead of height) of <5%. Children with TIS are also predisposed to sleep-related hypopneas (but not apneas) with recurrent hypoxemia during sleep and an increased arousal index [3]. This may also contribute to poor weight gain. The quality of life of children with TIS is worse than among children with asthma arthritis, and children awaiting heart transplantation [5]. Physical disability and burden of family care are the domains of the quality of life survey tools that are most affected by TIS. Late events can include pulmonary hypertension and cor pulmonale. Approximately 10% of the 320 children who underwent surgical therapy with the vertical expandible titanium prosthetic rib (VEPTR) were ventilator-dependent when first assessed for surgical therapy. Where once the outcome of these children was considered poor if the chest wall were small or the spine deformity progressed, the advent of new surgical spine and thoracic devices has transformed this population of children into a new group with chronic restrictive non-progressive respiratory disease. There are few studies of natural history of TIS conditions reported in the literature. The most quoted study is by Pehrsson et al using a national health database to determine mortality in high risk subgroups of adults with scoliosis [6]. The data is complicated by inclusion of neuromuscular weakness syndromes (including poliomyelitis) in addition to primary spinal structural deformities. With this caveat, the authors found that mortality due to early onset scoliosis (beginning at <8 years of age) increased beginning at 40 years of age and worsened thereafter. The concept put forth is that lung growth never reached normal values when postnatal growth of the lung and thorax were complete and that subsequent changes in lung function due to aging then impacted these people with diminished pulmonary reserve due to underlying restrictive pulmonary changes.