- Email: [email protected]
Casting a look at pediatric plastic bronchitis
G Model
PEDOT-7669; No. of Pages 4 International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Casting a look at pediatric plastic bronchitis Tin Jasinovic a,*, Frederick K. Kozak a, J. Paul Moxham a, Mark Chilvers b, David Wensley b, Michael Seear b, Andrew Campbell c, Jeffrey P. Ludemann a a
Division of Pediatric Otolaryngology, British Columbia’s Children’s Hospital, Vancouver, BC, Canada Division of Pediatric Respirology, British Columbia’s Children’s Hospital, Vancouver, BC, Canada c Division of Pediatric Cardiac Surgery, British Columbia’s Children’s Hospital, Vancouver, BC, Canada b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 May 2015 Received in revised form 3 July 2015 Accepted 4 July 2015 Available online xxx
Objectives: To review clinical presentations and management strategies for children with plastic bronchitis. Methods: Retrospective chart review. Results: Seven patients required rigid bronchoscopy to remove bronchial casts over a 17-year study period. Mean age at presentation was 60 months. Mean follow-up was 53 months. Co-morbidities included: congenital heart disease (n = 3), chronic pulmonary disorders (n = 2) and sickle cell disease (n = 1). 4 patients required multiple bronchoscopies for recurrent casts. Adjunctive topical therapies were administered in all 7 patients, without complication. Rigid bronchoscopy for cast removal was performed in 2 patients who were on extra-corporal membrane oxygenation (ECMO), using special precautions to safeguard the ECMO catheters. Conclusions: Bronchial casts in children may present acutely or sub-acutely. Recurrent casts are unusual; however, in combination with severe cardiac disease may lead to mortality. Adjunctive topical therapies are still under investigation. Special safeguards for ECMO catheters are imperative. This case series complements and adds to the International Plastic Bronchitis Registry. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Plastic bronchitis Bronchial casts Rigid bronchoscopy ECMO
1. Introduction Plastic bronchitis (PB) is a rare, but potentially fatal disease which was initially described as a collection of blood vessels (‘‘venae arteriosae expectorati’’) by Claudius Galen (131–200 AD). Not until 1750 did Bussie`re establish that PB is a consequence of inspissated bronchial secretions [1]. Official nomenclature of PB has evolved throughout history—including names such a fibrinous bronchitis [2], bronchitis pseudomembranosa [1], bronchial casts, Hoffman’s bronchitis [3], mucoid impaction [4] and bronchocentric granulomatosis [5]. Prior to 2008, less than five hundred cases of PB were reported in the English literature [6]. In 1997, the first formal histological classification was established to help clinicians understand and more effectively manage PB. The classification consisted of two types: type 1 casts were characterized by inflammatory cells and composed of fibrin and acute-phase inflammatory cell infiltrates, while type 2 casts were largely acellular and composed primarily
* Corresponding author. Tel.: +1 6 04 875 2113; fax: +1 6 04 875 2498. E-mail address: [email protected] (T. Jasinovic).
of mucin [7]. More recently, Kunder et al. have shown that a certain subset of casts do not fit in Seear’s histopathologic classification [8]. It has been postulated by Brogan et al. that Kunder’s histopathologic classification is strongly correlated with clinical history and presentation; type 1 casts being more commonly associated with inflammatory diseases of the lung while type 2 casts usually occurring in patients with severe cyanotic heart disease [9]. In adults with PB, a subset develop PB secondary to pulmonary lymphangiectasia whereas PB of non-lymphatic origin is mainly seen in the pediatric population [10]. Reported mean ages for children with PB range from 4 to 12 years; approximately 40% have congenital heart disease (CHD) [10]. In general, PB with CHD is more common in early childhood, compared to patients with non-cardiac comorbidities [10]. Reported acute mortality rates for PB have ranged over the past 15 years from 5% to 60% [6,10]. Historically, patients with PB and associated CHD have had a higher mortality rate than patients with other associated diseases [6,10]. Fig. 1 depicts a typically arborizing bronchial cast. In addition to removal of the casts by rigid laryngobronchoscopy (RLB), management of underlying cardiac, pulmonary and/or hematologic disease is an essential element of overall PB management [9].
http://dx.doi.org/10.1016/j.ijporl.2015.07.011 0165-5876/ß 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: T. Jasinovic, et al., Casting a look at pediatric plastic bronchitis, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.07.011
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PEDOT-7669; No. of Pages 4 T. Jasinovic et al. / International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
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Fig. 1. Typical plastic bronchitis branching pattern (Courtesy of F. Kozak). Fig. 2. Hematoxylin & eosin (H&E)-stained micrograph showing Charcot–Leyden crystals (black solid arrow) and eosinophilic granulocytes (white striped arrow) removed from a 27-month-old boy with recurrent asthma (40 objective).
2. Methods 2.1. Index case Patients with PB usually present acutely and require intensive medical and surgical care; however not all cases follow this clinical pattern [6]. To help illustrate variances in natural history, an index case in which the bronchial casts were unusually indolent (yet recurred several times) is presented. A twelve year old male with a history of cystic fibrosis (CF) and allergic bronchopulmonary aspergillosis (APBA) presented to the Respiratory Clinic at British Columbia’s Children’s Hospital (BCCH). He complained of progressive dyspnea and epigastric pain, but remained ambulatory. Chest radiographs showed evidence of right lower lobe atelectasis. There was no history or radiologic sign of an inhaled foreign body. Hospital admission was recommended, however the patient’s parents preferred to increase outpatient physiotherapy, instead. Five days later, the patient returned with worsening symptoms. His chest radiographs had not improved; he was therefore admitted for IV antibiotic therapy (Tobramycin, Meropenam) and the Otolaryngology service was consulted. Just prior to rigid laryngobronchoscopy (RLB), the patient was treated with inhaled dornase alpha 2.5 mg/day (Pulmozyme1, recombinant phosphorylated and glycosylated human deoxyribonuclease 1 protein). During the RLB, thick pale yellow obstructive plugs were removed from the right main bronchus using optical forceps and rigid suction. Histological examination revealed a largely mucin based framework, mixed with numerous granulocytic neutrophils. Bacterial cultures were positive for Burkholderia capacia; fungal cultures were negative. The patient’s respiratory status improved dramatically and he was discharged 8 days following the procedure. He remained asymptomatic for 4 months until he presented again with similar symptoms and radiographic findings. His subsequent RLB and hospitalization was markedly similar to those during his initial presentation. This clinical scenario recurred once again 32 months later (36 months after his initial presentation). He has had no further recurrence over the last 40 months.
After managing this case and several other cases of PB (recurrent and non-recurrent), it was concluded that a new case series and literature review was warranted for the following reasons: (1) the index case contrasted significantly to all of the other, more acute cases of PB managed in the previous seventeen years; (2) it was important to report certain safety measures for bronchoscopy for patients on extracorporeal membrane oxygenation (ECMO); (3) following the publication by Seear et al. [7], many promising potential new adjunctive therapies (AT) for PB have emerged, with varying levels of scientific evidence. Following IRB approval a retrospective chart review was conducted of all patients treated for PB at the BCCH from January 1998 to February 2015. For the purposes of this study, PB was defined as solid or semisolid (gel) bronchial material, which required rigid bronchoscopic instruments to be removed. 3. Results Table 1 outlines the results of our review of the seven patients diagnosed over the 17 year retrospective review period. The mean age was 5 years; all patients underwent RLB for PB (cast) removal. Associated diagnoses for these patients included cystic fibrosis (CF), allergic brochopulmonary aspergillosis (ABPA), congenital heart disease (CHD), asthma and sickle cell disease. In addition to cast removal, all patients received intesive respiratory supportive care as well as adjunctive therapy, including one or more of the following: inhaled corticosteriods (7), N-acetylscysteine (6), dornase alfa (1), hydroxyurea (1) and tissue plasminogen activator (tPA)(1). Histopathology for selected patients is displayed in Figs. 2 and 3. At a mean follow up of 53 months, three out of the seven patients in this series have had no recurrence. Besides the index case, three other patients had PB recurrences, as detailed below.
Table 1 Patient demographics, clinical presentation, treatment and outcomes. Age (mo)
Gender
Condition
Associated diagnoses
Cast characteristics
Histopathology
Year of initial Dx
Adjunctive therapies
Episodes
Survival (Y/N)
151 56
M M
Ambula-tory Critical
CF, ABPA CHD
Inflammatory (Type 1) Acellular (Type 2)
2008 2009
Dornase alfa N-acetyl cysteine
3 6
Y N
114
F
Critical
Sickle Cell
Thick, yellow mucoid Thick, complete fibrinous cast Golden ‘‘gel-like’’ material
Inflammatory (Type 1)
2011
2
Y
77 27 8 9
M M M M
Critical Critical Critical Critical
CHD Asthma CHD None
Pink semi-solid secretions Like ‘‘microwave chicken’’ Thick, yellow mucoid Pale, yellow ‘‘mollases’’
Acellular (Type 2) Inflammatory (Type 1) Acellular (Type 2) Inflammatory (Type 1)
2012 2006 2012 2012
Cortico-steroids, hydroxyurea Inhaled tPA Cortico-steroids N-acetyl cysteine Cortico-steroids
2 None None None
Y Y Y Y
Please cite this article in press as: T. Jasinovic, et al., Casting a look at pediatric plastic bronchitis, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.07.011
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PEDOT-7669; No. of Pages 4 T. Jasinovic et al. / International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
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In summary, four patients had recurrences and required a total of 13 RLBs—ranging from two to six per patient. 4. Discussion
Fig. 3. H&E stained micrograph of a hypocellular, fibrinous cast removed from a 9 month old boy with idiopathic plastic bronchitis (10 objective).
3.1. Case #2 A four and a half year old male with a history of hypoplastic left heart disease, previously managed with a Fontan procedure was admitted with acute respiratory failure. Chest X-ray on admission revealed widespead left-sided atelectasis. RLB revelead a solid cast, which was subsequently removed. Over the subsequent three months, six RLBs were performed to remove recurrent casts, four of which were during one hospital admission. Despite maximal therapy, the patient expired shortly after the last RLB due to severe, surgically uncorrectable cardiopulmonary disease. This occurred in the era prior to topical tPA administration. 3.2. Case #3 A nine and half year old female with a documented history of sickle cell disease presented to the emergency room with acute chest syndrome (ACS). (Potentially fatal, ACS is a vaso-occlusive crisis of the pulmonary vasculature, characterized by a new infiltrate on chest X-ray plus the new onset of severe chest pain, fever, cough, sputum production, dyspnea and/or hypoxia. [11] Hydroxyurea is a recommended treatment for ACS and functions by an unknown mechanism to breakdown cells that are prone to sickle and also increases fetal hemoglobin) [12]. Despite prompt management with hydroxyurea and inhaled corticosteroids, this patient required two RLBs over the span of one week to remove golden, gel-like casts from her left mainstem bronchus. She has had no further recurrences or relevant hospital admissions over the subsequent 40 months. 3.3. Case #4 A six and a half year old male with a history of congenital hypoplastic right ventricle and dextrocardia underwent emergent RLB after chest X-rays revealed a complete ‘‘whiteout’’ of his right lung, where numerous pink sputum aggregations were removed. Portions of the lower lobe were inaccessible; therefore concurrent tissue plasminogen activator (tPA) was topically administered. (Developed in the early 1980s, tPA is a recombinant endothelial cell serine protease which functions within the fibrinolytic cascade by catalyzing the conversion of plasminogen to plasmin) [13]. Despite initial treatment, the patient required ECMO due to his deteriorating cardiac function. He required repeat RLB the following day while still on ECMO. In total three RLBs were done over a span of eight months; topical tPA was effective in improving the outcome on each occasion. The patient has been followed-up for 30 months after the last RLB and no recurrences have been noted.
While bronchial casts can present at any stage in life, they are more commonly seen in the pediatric population [10]. In adults, semi-solid (gel) bronchial material can often be removed via flexible bronchoscopy; however, in young children, airway caliber may necessitate the use of a rigid bronchoscope and straight suctions of varying diameter, plus or minus optical forceps. In this series of pediatric PB, we examined only cases, which required rigid bronchoscopic removal. Our results revealed a male predilection, which only occasionally has been reported in other case series [8]. However, our patients shared most other commonly reported epidemiological characteristics such as: mean age, mortality rate and associated diagnoses [10,14]. Fig. 2 illustrates a type 1 cast with Charcot– Leiden crystals, which form from after the lysis of eosinophils and are characteristic of allergic pulmonary inflammation (secondary to asthma or parasitic infection). Type 2 casts are typically acellular or hypocellular, as depicted in Fig. 3. Type 2 casts are more likely to be recurrent than type 1 casts [6]. Most, but not all children with PB require urgent hospital admission with intensive medical and surgical care. Schumacher et al. recently reported regarding 46 children who developed PB after Fontan procedure: while 9% did not require hospital admission, most patients required multiple hospital admissions (and 7% required more than 20 hospital admissions for PB) [14]. In our series, 88% of patients had an acute presentation, requiring intensive medical and surgical care. Our index case illustrates that a patient with type 1 bronchial casts may also have an insidious and recurrent clinical course. 4.1. Special considerations PB patients on ECMO should have their bronchoscopy in the ICU whenever possible. The risk of transport of a pediatric patient with PB on ECMO to the operating room (OR) may be greater than the benefit. Transport to the OR will not only delay the procedure, but also potentially place a unstable patient at risk of vascular shearing and potential embolization within the cervical ECMO catheters. It is recommended that during the procedure one team member should manually stabilize the catheters for improved safety. 4.2. Review of current therapy Despite histological classification, PB has significant variance in terms of pathogenesis, histology and natural history. PB may also vary in its physical properties (such as solidity and elasticity). Rigid bronchoscopy, along with intensive medical support remains the mainstay of definitive therapy for PB in an acute setting. For the rare patient with PB who is not considered to be a candidate for bronchoscopy, some evidence exists that high frequency jet ventilation and chest physiotherapy be employed for possible disruption and subsequent clearance of casts [15]. Prevention of cast recurrence is also an important therapeutic objective. This may be more likely with certain adjunctive therapies (AT). Because of this variance and the rarity of PB, certain areas of scientific understanding of AT have been lacking. A multitude of case reports and small case series have been published, most presenting anecdotal success in various treatment modalities including: mucolytics (such as inhaled acetylcysteine/dornase alfa) [16–20], fibrinolytics (such as aerosolized heparin/urokinase [19], topically inhaled corticosteroids, thoracic duct ligation [20], and hypertonic saline, in conjunction with respiratory therapy [21]. The use of
Please cite this article in press as: T. Jasinovic, et al., Casting a look at pediatric plastic bronchitis, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.07.011
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topical (intratracheal) tPA for lysis of hypocellular casts, as seen in cardiac patients, was initially reported by Costello et al. in 2002; its therapeutic index in this subset of patients with PB continues to be analyzed [22–24]. Surprisingly, topical tPA was also reported to be effective for a six year old with eosinophilic PB, after other therapies had failed [25]. Topical tPA carries a theoretical risk of pulmonary hemorrhage however this complication has not been reported in humans with PB. Despite this, there is still no scientific consensus regarding optimal AT strategies for other subsets of patients with PB. Recurrence rates and overall mortality remain high. Hopefully, through collaborative efforts, such as the International Plastic Bronchitis Registry, we will soon attain an improved understanding of the various, underlying bronchial hypersecretory processes and discover targeted, evidence-based ATs for PB. 5. Conclusions PB is a rare, highly variable and potentially fatal disease, which arises from numerous pathologic mechanisms. Although most cases present acutely, some patients with PB may be ambulatory. Both acute and subacute PB may be recurrent. Despite suggestions of more than a dozen ATs in the literature, none have strong (level 1 or 2) scientific evidence supporting their use. Extra safety precautions should be undertaken in dealing with patients on ECMO. To date, topical tPA administration seems the most promising AT in cast variants showing hypocellular and fibrin composition. Overall the level of clinical evidence remains low; however, initiatives like the International Plastic Bronchitis Registry are promising. Further international collaborative research is needed to unravel bronchial cast pathophysiology and determine optimal, individualized AT strategies. Acknowledgments We thank Dr. Oana Popescu for providing histopathology images and interpretation. References [1] A. Muller, A. Mithal, A case of plastic bronchitis, J. R. Soc. Med. 81 (1998) 360. [2] M. Bettmann, Report of a case of fibrinous bronchitis with a review of all cases in the literature, Am. J. Med. Sci. 123 (1902) 304–329. [3] P.B. Mulligan, R.D. Spencer, Chronic fibrinous bronchitis as a symptom of mediastinal compression, JAMA 82 (1924) 791–792.
[4] P.B. Woolley, Massive atelectasis due to fibrinous bronchitis, Thorax 8 (1953) 301–302. [5] R.R. Shaw, Mucoid impaction of the bronchi, J. Thorac. Surg. 22 (1951) 149–163. [6] M.H. Eberlein, M.B. Drummond, E.F. Haponik, Plastic bronchitis: a management challenge, Am. J. Med. Sci. 335 (2) (2008) 163–169. [7] M. Seear, H. Hui, F. Magee, D. Bohn, E. Cutz, Bronchial casts in children: a proposed classification based on nine cases and a review of the literature, Am. J. Respir. Crit. Care Med. 155 (1997) 364–370. [8] R. Kunder, C. Kunder, H.Y. Sun, G. Berry, A. Messner, J. Frankovich, et al., Pediatric plastic bronchitis: case report and retrospective comparative analysis of epidemiology and pathology, Case Rep. Pulmonol. 40 (2013) 649365. [9] T.V. Brogan, L.S. Finn, D.J. Pyskaty Jr., G.J. Redding, D. Ricker, A. Inglis, et al., Plastic bronchitis in children: a case series and review of the medical literature, Pediatr. Pulmonol. 34 (6) (2002) 482–487. [10] P. Madsen, S.A. Shah, B.K. Rubin, Plastic bronchitis: new insights and a classification scheme, Paediatr. Respir. Rev. 6 (4) (2005) 292–300. [11] H.A. Abbas, M. Kahale, M.A. Hosn, A. Inati, A review of acute chest syndrome in pediatric sickle cell disease, Pediatr. Ann. 42 (3) (2013) 115–120. [12] S. Lanzkron, J.J. Strouse, R. Wilson, M.C. Beach, C. Haywood, H. Park, et al., Systematic review: hydroxyurea for the treatment of adults with sickle cell disease, Ann. Intern. Med. 148 (2008) 939–955. [13] D. Collen, H.R. Linjen, The tissue-type plasminogen activator story, Arterioscler. Thromb. Vasc. Biol. 29 (2009) 1151–1155. [14] K.R. Schumacher, K.A. Stringer, J.E. Donahue, S. Yu, A. Shaver, R.L. Caruthers, et al., Fontan-associated protein-losing enteropathy and plastic bronchitis, J. Pediatr. 166 (4) (2015), 979-977. [15] M. Zahorec, L. Kovacikova, P. Martanovic, P. Skrak, P. Kunovsky, The use of highfrequency jet ventilation for removal of obstructing casts in patients with plastic bronchitis, Pediatr. Crit. Care Med. 10 (3) (2009) e34–e36. [16] S.S. Manna, J. Shaw, S.M. Tibby, A. Durward, Treatment of plastic bronchitis in acute chest syndrome of sickle cell disease with intratracheal rhDNase, Arch. Dis. Child. 88 (7) (2003) 626–627. [17] J. Schmitz, J. Schatz, D. Kirsten, Plastic bronchitis, Pneumologie 58 (6) (2004) 443–448. [18] R.C. Silva, J.P. Simons, D.H. Chi, R.F. Yellon, C.M. Alper, Endoscopic treatment of plastic bronchitis, Arch. Otolaryngol. Head Neck Surg. 137 (4) (2011) 401–403. [19] M.W. Quasney, K. Orman, J. Thompson, J.C. Ring, M. Salim, R.A. Schoumacher, et al., Plastic bronchitis occurring late after the Fontan procedure: treatment with aerosolized urokinase, Crit. Care Med. 28 (6) (2000) 2107–2111. [20] J. Languepin, P. Scheinmann, B. Mahut, M. Bourgeois, F. Jaubert, F. Brunelle, et al., Bronchial casts in children with cardiopathies: the role of pulmonary lymphatic abnormalities, Pediatr. Pulmonol. 28 (5) (1999) 329–336. [21] M. Berlucchi, F. Pelucchi, S. Timpano, A. Zorzi, R. Padoan, A conservative treatment for plastic bronchitis in pediatric age, Am. J. Otolaryngol. 35 (2) (2014) 204–206. [22] J.M. Costello, D. Steinhorn, S. McColley, M.E. Gerber, S.P. Kumar, Treatment of plastic bronchitis in a Fontan patient with tissue plasminogen activator: a case report and review of the literature, J. Pediatr. 109 (2002) e67. [23] T.B. Do, J.M. Chu, F. Berdjis, N.G. Anas, Fontan patient with plastic bronchitis treated successfully using aerosolized tissue plasminogen activator: a case report and review of the literature, Pediatr. Cardiol. 30 (3) (2009) 352–355. [24] M.K. Wakeham, A.H. Van Bergen, L.E. Torero, J. Akhter, Long-term treatment of plastic bronchitis with aerosolized tissue plasminogen activator in a Fontan patient, Pediatr. Crit. Care Med. 6 (1) (2005) 76–78. [25] E. Gibb, R. Blount, N. Lewis, D. Nielson, G. Church, K. Jones, et al., Management of plastic bronchitis with topical tissue-type plasminogen activator, J. Pediatr. 130 (2) (2012) e446–e450.
Please cite this article in press as: T. Jasinovic, et al., Casting a look at pediatric plastic bronchitis, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.07.011
PEDOT-7669; No. of Pages 4 International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Casting a look at pediatric plastic bronchitis Tin Jasinovic a,*, Frederick K. Kozak a, J. Paul Moxham a, Mark Chilvers b, David Wensley b, Michael Seear b, Andrew Campbell c, Jeffrey P. Ludemann a a
Division of Pediatric Otolaryngology, British Columbia’s Children’s Hospital, Vancouver, BC, Canada Division of Pediatric Respirology, British Columbia’s Children’s Hospital, Vancouver, BC, Canada c Division of Pediatric Cardiac Surgery, British Columbia’s Children’s Hospital, Vancouver, BC, Canada b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 May 2015 Received in revised form 3 July 2015 Accepted 4 July 2015 Available online xxx
Objectives: To review clinical presentations and management strategies for children with plastic bronchitis. Methods: Retrospective chart review. Results: Seven patients required rigid bronchoscopy to remove bronchial casts over a 17-year study period. Mean age at presentation was 60 months. Mean follow-up was 53 months. Co-morbidities included: congenital heart disease (n = 3), chronic pulmonary disorders (n = 2) and sickle cell disease (n = 1). 4 patients required multiple bronchoscopies for recurrent casts. Adjunctive topical therapies were administered in all 7 patients, without complication. Rigid bronchoscopy for cast removal was performed in 2 patients who were on extra-corporal membrane oxygenation (ECMO), using special precautions to safeguard the ECMO catheters. Conclusions: Bronchial casts in children may present acutely or sub-acutely. Recurrent casts are unusual; however, in combination with severe cardiac disease may lead to mortality. Adjunctive topical therapies are still under investigation. Special safeguards for ECMO catheters are imperative. This case series complements and adds to the International Plastic Bronchitis Registry. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Plastic bronchitis Bronchial casts Rigid bronchoscopy ECMO
1. Introduction Plastic bronchitis (PB) is a rare, but potentially fatal disease which was initially described as a collection of blood vessels (‘‘venae arteriosae expectorati’’) by Claudius Galen (131–200 AD). Not until 1750 did Bussie`re establish that PB is a consequence of inspissated bronchial secretions [1]. Official nomenclature of PB has evolved throughout history—including names such a fibrinous bronchitis [2], bronchitis pseudomembranosa [1], bronchial casts, Hoffman’s bronchitis [3], mucoid impaction [4] and bronchocentric granulomatosis [5]. Prior to 2008, less than five hundred cases of PB were reported in the English literature [6]. In 1997, the first formal histological classification was established to help clinicians understand and more effectively manage PB. The classification consisted of two types: type 1 casts were characterized by inflammatory cells and composed of fibrin and acute-phase inflammatory cell infiltrates, while type 2 casts were largely acellular and composed primarily
* Corresponding author. Tel.: +1 6 04 875 2113; fax: +1 6 04 875 2498. E-mail address: [email protected] (T. Jasinovic).
of mucin [7]. More recently, Kunder et al. have shown that a certain subset of casts do not fit in Seear’s histopathologic classification [8]. It has been postulated by Brogan et al. that Kunder’s histopathologic classification is strongly correlated with clinical history and presentation; type 1 casts being more commonly associated with inflammatory diseases of the lung while type 2 casts usually occurring in patients with severe cyanotic heart disease [9]. In adults with PB, a subset develop PB secondary to pulmonary lymphangiectasia whereas PB of non-lymphatic origin is mainly seen in the pediatric population [10]. Reported mean ages for children with PB range from 4 to 12 years; approximately 40% have congenital heart disease (CHD) [10]. In general, PB with CHD is more common in early childhood, compared to patients with non-cardiac comorbidities [10]. Reported acute mortality rates for PB have ranged over the past 15 years from 5% to 60% [6,10]. Historically, patients with PB and associated CHD have had a higher mortality rate than patients with other associated diseases [6,10]. Fig. 1 depicts a typically arborizing bronchial cast. In addition to removal of the casts by rigid laryngobronchoscopy (RLB), management of underlying cardiac, pulmonary and/or hematologic disease is an essential element of overall PB management [9].
http://dx.doi.org/10.1016/j.ijporl.2015.07.011 0165-5876/ß 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: T. Jasinovic, et al., Casting a look at pediatric plastic bronchitis, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.07.011
G Model
PEDOT-7669; No. of Pages 4 T. Jasinovic et al. / International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
2
Fig. 1. Typical plastic bronchitis branching pattern (Courtesy of F. Kozak). Fig. 2. Hematoxylin & eosin (H&E)-stained micrograph showing Charcot–Leyden crystals (black solid arrow) and eosinophilic granulocytes (white striped arrow) removed from a 27-month-old boy with recurrent asthma (40 objective).
2. Methods 2.1. Index case Patients with PB usually present acutely and require intensive medical and surgical care; however not all cases follow this clinical pattern [6]. To help illustrate variances in natural history, an index case in which the bronchial casts were unusually indolent (yet recurred several times) is presented. A twelve year old male with a history of cystic fibrosis (CF) and allergic bronchopulmonary aspergillosis (APBA) presented to the Respiratory Clinic at British Columbia’s Children’s Hospital (BCCH). He complained of progressive dyspnea and epigastric pain, but remained ambulatory. Chest radiographs showed evidence of right lower lobe atelectasis. There was no history or radiologic sign of an inhaled foreign body. Hospital admission was recommended, however the patient’s parents preferred to increase outpatient physiotherapy, instead. Five days later, the patient returned with worsening symptoms. His chest radiographs had not improved; he was therefore admitted for IV antibiotic therapy (Tobramycin, Meropenam) and the Otolaryngology service was consulted. Just prior to rigid laryngobronchoscopy (RLB), the patient was treated with inhaled dornase alpha 2.5 mg/day (Pulmozyme1, recombinant phosphorylated and glycosylated human deoxyribonuclease 1 protein). During the RLB, thick pale yellow obstructive plugs were removed from the right main bronchus using optical forceps and rigid suction. Histological examination revealed a largely mucin based framework, mixed with numerous granulocytic neutrophils. Bacterial cultures were positive for Burkholderia capacia; fungal cultures were negative. The patient’s respiratory status improved dramatically and he was discharged 8 days following the procedure. He remained asymptomatic for 4 months until he presented again with similar symptoms and radiographic findings. His subsequent RLB and hospitalization was markedly similar to those during his initial presentation. This clinical scenario recurred once again 32 months later (36 months after his initial presentation). He has had no further recurrence over the last 40 months.
After managing this case and several other cases of PB (recurrent and non-recurrent), it was concluded that a new case series and literature review was warranted for the following reasons: (1) the index case contrasted significantly to all of the other, more acute cases of PB managed in the previous seventeen years; (2) it was important to report certain safety measures for bronchoscopy for patients on extracorporeal membrane oxygenation (ECMO); (3) following the publication by Seear et al. [7], many promising potential new adjunctive therapies (AT) for PB have emerged, with varying levels of scientific evidence. Following IRB approval a retrospective chart review was conducted of all patients treated for PB at the BCCH from January 1998 to February 2015. For the purposes of this study, PB was defined as solid or semisolid (gel) bronchial material, which required rigid bronchoscopic instruments to be removed. 3. Results Table 1 outlines the results of our review of the seven patients diagnosed over the 17 year retrospective review period. The mean age was 5 years; all patients underwent RLB for PB (cast) removal. Associated diagnoses for these patients included cystic fibrosis (CF), allergic brochopulmonary aspergillosis (ABPA), congenital heart disease (CHD), asthma and sickle cell disease. In addition to cast removal, all patients received intesive respiratory supportive care as well as adjunctive therapy, including one or more of the following: inhaled corticosteriods (7), N-acetylscysteine (6), dornase alfa (1), hydroxyurea (1) and tissue plasminogen activator (tPA)(1). Histopathology for selected patients is displayed in Figs. 2 and 3. At a mean follow up of 53 months, three out of the seven patients in this series have had no recurrence. Besides the index case, three other patients had PB recurrences, as detailed below.
Table 1 Patient demographics, clinical presentation, treatment and outcomes. Age (mo)
Gender
Condition
Associated diagnoses
Cast characteristics
Histopathology
Year of initial Dx
Adjunctive therapies
Episodes
Survival (Y/N)
151 56
M M
Ambula-tory Critical
CF, ABPA CHD
Inflammatory (Type 1) Acellular (Type 2)
2008 2009
Dornase alfa N-acetyl cysteine
3 6
Y N
114
F
Critical
Sickle Cell
Thick, yellow mucoid Thick, complete fibrinous cast Golden ‘‘gel-like’’ material
Inflammatory (Type 1)
2011
2
Y
77 27 8 9
M M M M
Critical Critical Critical Critical
CHD Asthma CHD None
Pink semi-solid secretions Like ‘‘microwave chicken’’ Thick, yellow mucoid Pale, yellow ‘‘mollases’’
Acellular (Type 2) Inflammatory (Type 1) Acellular (Type 2) Inflammatory (Type 1)
2012 2006 2012 2012
Cortico-steroids, hydroxyurea Inhaled tPA Cortico-steroids N-acetyl cysteine Cortico-steroids
2 None None None
Y Y Y Y
Please cite this article in press as: T. Jasinovic, et al., Casting a look at pediatric plastic bronchitis, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.07.011
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3
In summary, four patients had recurrences and required a total of 13 RLBs—ranging from two to six per patient. 4. Discussion
Fig. 3. H&E stained micrograph of a hypocellular, fibrinous cast removed from a 9 month old boy with idiopathic plastic bronchitis (10 objective).
3.1. Case #2 A four and a half year old male with a history of hypoplastic left heart disease, previously managed with a Fontan procedure was admitted with acute respiratory failure. Chest X-ray on admission revealed widespead left-sided atelectasis. RLB revelead a solid cast, which was subsequently removed. Over the subsequent three months, six RLBs were performed to remove recurrent casts, four of which were during one hospital admission. Despite maximal therapy, the patient expired shortly after the last RLB due to severe, surgically uncorrectable cardiopulmonary disease. This occurred in the era prior to topical tPA administration. 3.2. Case #3 A nine and half year old female with a documented history of sickle cell disease presented to the emergency room with acute chest syndrome (ACS). (Potentially fatal, ACS is a vaso-occlusive crisis of the pulmonary vasculature, characterized by a new infiltrate on chest X-ray plus the new onset of severe chest pain, fever, cough, sputum production, dyspnea and/or hypoxia. [11] Hydroxyurea is a recommended treatment for ACS and functions by an unknown mechanism to breakdown cells that are prone to sickle and also increases fetal hemoglobin) [12]. Despite prompt management with hydroxyurea and inhaled corticosteroids, this patient required two RLBs over the span of one week to remove golden, gel-like casts from her left mainstem bronchus. She has had no further recurrences or relevant hospital admissions over the subsequent 40 months. 3.3. Case #4 A six and a half year old male with a history of congenital hypoplastic right ventricle and dextrocardia underwent emergent RLB after chest X-rays revealed a complete ‘‘whiteout’’ of his right lung, where numerous pink sputum aggregations were removed. Portions of the lower lobe were inaccessible; therefore concurrent tissue plasminogen activator (tPA) was topically administered. (Developed in the early 1980s, tPA is a recombinant endothelial cell serine protease which functions within the fibrinolytic cascade by catalyzing the conversion of plasminogen to plasmin) [13]. Despite initial treatment, the patient required ECMO due to his deteriorating cardiac function. He required repeat RLB the following day while still on ECMO. In total three RLBs were done over a span of eight months; topical tPA was effective in improving the outcome on each occasion. The patient has been followed-up for 30 months after the last RLB and no recurrences have been noted.
While bronchial casts can present at any stage in life, they are more commonly seen in the pediatric population [10]. In adults, semi-solid (gel) bronchial material can often be removed via flexible bronchoscopy; however, in young children, airway caliber may necessitate the use of a rigid bronchoscope and straight suctions of varying diameter, plus or minus optical forceps. In this series of pediatric PB, we examined only cases, which required rigid bronchoscopic removal. Our results revealed a male predilection, which only occasionally has been reported in other case series [8]. However, our patients shared most other commonly reported epidemiological characteristics such as: mean age, mortality rate and associated diagnoses [10,14]. Fig. 2 illustrates a type 1 cast with Charcot– Leiden crystals, which form from after the lysis of eosinophils and are characteristic of allergic pulmonary inflammation (secondary to asthma or parasitic infection). Type 2 casts are typically acellular or hypocellular, as depicted in Fig. 3. Type 2 casts are more likely to be recurrent than type 1 casts [6]. Most, but not all children with PB require urgent hospital admission with intensive medical and surgical care. Schumacher et al. recently reported regarding 46 children who developed PB after Fontan procedure: while 9% did not require hospital admission, most patients required multiple hospital admissions (and 7% required more than 20 hospital admissions for PB) [14]. In our series, 88% of patients had an acute presentation, requiring intensive medical and surgical care. Our index case illustrates that a patient with type 1 bronchial casts may also have an insidious and recurrent clinical course. 4.1. Special considerations PB patients on ECMO should have their bronchoscopy in the ICU whenever possible. The risk of transport of a pediatric patient with PB on ECMO to the operating room (OR) may be greater than the benefit. Transport to the OR will not only delay the procedure, but also potentially place a unstable patient at risk of vascular shearing and potential embolization within the cervical ECMO catheters. It is recommended that during the procedure one team member should manually stabilize the catheters for improved safety. 4.2. Review of current therapy Despite histological classification, PB has significant variance in terms of pathogenesis, histology and natural history. PB may also vary in its physical properties (such as solidity and elasticity). Rigid bronchoscopy, along with intensive medical support remains the mainstay of definitive therapy for PB in an acute setting. For the rare patient with PB who is not considered to be a candidate for bronchoscopy, some evidence exists that high frequency jet ventilation and chest physiotherapy be employed for possible disruption and subsequent clearance of casts [15]. Prevention of cast recurrence is also an important therapeutic objective. This may be more likely with certain adjunctive therapies (AT). Because of this variance and the rarity of PB, certain areas of scientific understanding of AT have been lacking. A multitude of case reports and small case series have been published, most presenting anecdotal success in various treatment modalities including: mucolytics (such as inhaled acetylcysteine/dornase alfa) [16–20], fibrinolytics (such as aerosolized heparin/urokinase [19], topically inhaled corticosteroids, thoracic duct ligation [20], and hypertonic saline, in conjunction with respiratory therapy [21]. The use of
Please cite this article in press as: T. Jasinovic, et al., Casting a look at pediatric plastic bronchitis, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.07.011
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topical (intratracheal) tPA for lysis of hypocellular casts, as seen in cardiac patients, was initially reported by Costello et al. in 2002; its therapeutic index in this subset of patients with PB continues to be analyzed [22–24]. Surprisingly, topical tPA was also reported to be effective for a six year old with eosinophilic PB, after other therapies had failed [25]. Topical tPA carries a theoretical risk of pulmonary hemorrhage however this complication has not been reported in humans with PB. Despite this, there is still no scientific consensus regarding optimal AT strategies for other subsets of patients with PB. Recurrence rates and overall mortality remain high. Hopefully, through collaborative efforts, such as the International Plastic Bronchitis Registry, we will soon attain an improved understanding of the various, underlying bronchial hypersecretory processes and discover targeted, evidence-based ATs for PB. 5. Conclusions PB is a rare, highly variable and potentially fatal disease, which arises from numerous pathologic mechanisms. Although most cases present acutely, some patients with PB may be ambulatory. Both acute and subacute PB may be recurrent. Despite suggestions of more than a dozen ATs in the literature, none have strong (level 1 or 2) scientific evidence supporting their use. Extra safety precautions should be undertaken in dealing with patients on ECMO. To date, topical tPA administration seems the most promising AT in cast variants showing hypocellular and fibrin composition. Overall the level of clinical evidence remains low; however, initiatives like the International Plastic Bronchitis Registry are promising. Further international collaborative research is needed to unravel bronchial cast pathophysiology and determine optimal, individualized AT strategies. Acknowledgments We thank Dr. Oana Popescu for providing histopathology images and interpretation. References [1] A. Muller, A. Mithal, A case of plastic bronchitis, J. R. Soc. Med. 81 (1998) 360. [2] M. Bettmann, Report of a case of fibrinous bronchitis with a review of all cases in the literature, Am. J. Med. Sci. 123 (1902) 304–329. [3] P.B. Mulligan, R.D. Spencer, Chronic fibrinous bronchitis as a symptom of mediastinal compression, JAMA 82 (1924) 791–792.
[4] P.B. Woolley, Massive atelectasis due to fibrinous bronchitis, Thorax 8 (1953) 301–302. [5] R.R. Shaw, Mucoid impaction of the bronchi, J. Thorac. Surg. 22 (1951) 149–163. [6] M.H. Eberlein, M.B. Drummond, E.F. Haponik, Plastic bronchitis: a management challenge, Am. J. Med. Sci. 335 (2) (2008) 163–169. [7] M. Seear, H. Hui, F. Magee, D. Bohn, E. Cutz, Bronchial casts in children: a proposed classification based on nine cases and a review of the literature, Am. J. Respir. Crit. Care Med. 155 (1997) 364–370. [8] R. Kunder, C. Kunder, H.Y. Sun, G. Berry, A. Messner, J. Frankovich, et al., Pediatric plastic bronchitis: case report and retrospective comparative analysis of epidemiology and pathology, Case Rep. Pulmonol. 40 (2013) 649365. [9] T.V. Brogan, L.S. Finn, D.J. Pyskaty Jr., G.J. Redding, D. Ricker, A. Inglis, et al., Plastic bronchitis in children: a case series and review of the medical literature, Pediatr. Pulmonol. 34 (6) (2002) 482–487. [10] P. Madsen, S.A. Shah, B.K. Rubin, Plastic bronchitis: new insights and a classification scheme, Paediatr. Respir. Rev. 6 (4) (2005) 292–300. [11] H.A. Abbas, M. Kahale, M.A. Hosn, A. Inati, A review of acute chest syndrome in pediatric sickle cell disease, Pediatr. Ann. 42 (3) (2013) 115–120. [12] S. Lanzkron, J.J. Strouse, R. Wilson, M.C. Beach, C. Haywood, H. Park, et al., Systematic review: hydroxyurea for the treatment of adults with sickle cell disease, Ann. Intern. Med. 148 (2008) 939–955. [13] D. Collen, H.R. Linjen, The tissue-type plasminogen activator story, Arterioscler. Thromb. Vasc. Biol. 29 (2009) 1151–1155. [14] K.R. Schumacher, K.A. Stringer, J.E. Donahue, S. Yu, A. Shaver, R.L. Caruthers, et al., Fontan-associated protein-losing enteropathy and plastic bronchitis, J. Pediatr. 166 (4) (2015), 979-977. [15] M. Zahorec, L. Kovacikova, P. Martanovic, P. Skrak, P. Kunovsky, The use of highfrequency jet ventilation for removal of obstructing casts in patients with plastic bronchitis, Pediatr. Crit. Care Med. 10 (3) (2009) e34–e36. [16] S.S. Manna, J. Shaw, S.M. Tibby, A. Durward, Treatment of plastic bronchitis in acute chest syndrome of sickle cell disease with intratracheal rhDNase, Arch. Dis. Child. 88 (7) (2003) 626–627. [17] J. Schmitz, J. Schatz, D. Kirsten, Plastic bronchitis, Pneumologie 58 (6) (2004) 443–448. [18] R.C. Silva, J.P. Simons, D.H. Chi, R.F. Yellon, C.M. Alper, Endoscopic treatment of plastic bronchitis, Arch. Otolaryngol. Head Neck Surg. 137 (4) (2011) 401–403. [19] M.W. Quasney, K. Orman, J. Thompson, J.C. Ring, M. Salim, R.A. Schoumacher, et al., Plastic bronchitis occurring late after the Fontan procedure: treatment with aerosolized urokinase, Crit. Care Med. 28 (6) (2000) 2107–2111. [20] J. Languepin, P. Scheinmann, B. Mahut, M. Bourgeois, F. Jaubert, F. Brunelle, et al., Bronchial casts in children with cardiopathies: the role of pulmonary lymphatic abnormalities, Pediatr. Pulmonol. 28 (5) (1999) 329–336. [21] M. Berlucchi, F. Pelucchi, S. Timpano, A. Zorzi, R. Padoan, A conservative treatment for plastic bronchitis in pediatric age, Am. J. Otolaryngol. 35 (2) (2014) 204–206. [22] J.M. Costello, D. Steinhorn, S. McColley, M.E. Gerber, S.P. Kumar, Treatment of plastic bronchitis in a Fontan patient with tissue plasminogen activator: a case report and review of the literature, J. Pediatr. 109 (2002) e67. [23] T.B. Do, J.M. Chu, F. Berdjis, N.G. Anas, Fontan patient with plastic bronchitis treated successfully using aerosolized tissue plasminogen activator: a case report and review of the literature, Pediatr. Cardiol. 30 (3) (2009) 352–355. [24] M.K. Wakeham, A.H. Van Bergen, L.E. Torero, J. Akhter, Long-term treatment of plastic bronchitis with aerosolized tissue plasminogen activator in a Fontan patient, Pediatr. Crit. Care Med. 6 (1) (2005) 76–78. [25] E. Gibb, R. Blount, N. Lewis, D. Nielson, G. Church, K. Jones, et al., Management of plastic bronchitis with topical tissue-type plasminogen activator, J. Pediatr. 130 (2) (2012) e446–e450.
Please cite this article in press as: T. Jasinovic, et al., Casting a look at pediatric plastic bronchitis, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.07.011