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Intermittent Haemoptysis due to an Aortobronchial Fistula in a Warmblood Mare
J. Comp. Path. 2016, Vol. 155, 213e217
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SPONTANEOUSLY ARISING DISEASE
Intermittent Haemoptysis due to an Aortobronchial Fistula in a Warmblood Mare H. Versnaeyen*, V. Saey*, D. Vermeiren†, K. Chiers* and R. Ducatelle* * Department of Veterinary Pathology, Faculty of Veterinary Medicine, University of Ghent and † Veterinary Practice, Perbeemd, Sint-Lenaartseweg 67, Loenhout, Belgium
Summary A 7-year-old warmblood mare showed sudden onset of mild intermittent haemoptysis. Clinical examination revealed no significant abnormalities. Haematological examination showed mild anaemia, hypoalbuminaemia and neutrophilia. Coagulation tests were normal. Endoscopic examination revealed unilateral pulmonary haemorrhage with blood clots in the bronchi and trachea. Treatment with antibiotics was started and the horse was given stable rest. Two weeks later, the horse was found dead with blood and frothy sputum leaking from the nostrils. Post-mortem examination revealed a large thoracic aortic aneurysm communicating with a pseudoaneurysm that had formed a fistula into a right bronchial branch. Microscopical examination of the aneurysm showed extensive medial fibrosis with prominent degeneration, fragmentation and mineralization of the elastic fibres and deposition of mucoid material in the tunica media. The pseudoaneurysm was lined by collagen bundles admixed with fibroblasts and a small amount of adipose tissue. Aortobronchial fistula is a rare condition in man that is usually associated with primary aortic pathology, most often aneurysms. To the authors’ knowledge this is the first case of a fatal aortobronchial fistula in a horse or any other animal species. Ó 2016 Elsevier Ltd. All rights reserved. Keywords: aortic aneurysm; aortobronchial fistula; horse; pseudoaneurysm
Aortobronchial fistula is a rare condition characterized by the development of a communication between the aorta and a branch of the bronchial tree. This condition has only been described in man and to the best of our knowledge has never been observed in any animal species. In man, the mortality rate is 100% if left untreated (Wood et al., 1984; Fernandez-Gonzalez et al., 1996; MacIntosh et al., 1998; Posacioglu and Apaydin, 2004; Li et al., 2013). The clinical course in human patients is characterized by recurrent haemoptysis of varying severity, ranging from intermittent and minor to massive, with subsequent death. An underlying aneurysm is usually associated with this disease. An aneurysm is a localized abnormal dilation of any vessel. True aneurysms are composed of all or most layers of the intact vessel wall. False aneurysms, also called pseudoaneurysms, Correspondence to: H. Versnaeyen (e-mail: [email protected]). 0021-9975/$ - see front matter http://dx.doi.org/10.1016/j.jcpa.2016.07.007
result from rupture of an artery or aneurysm, with disruption of all three layers of the arterial wall and communication with the arterial lumen (Maxie and Robinson, 2015). As aortic aneurysms expand they exert pressure on the adjacent tracheobronchial tree with tissue necrosis and eventually breakdown of the intervening vascular and bronchial walls, allowing direct communication between the circulation and the lumen of the upper airways (Li et al., 2013). In horses, aortic aneurysms are typically located abdominally and are often associated with Strongylus vulgaris arteritis (Simoens et al., 1999). Strongyles may also move up the thoracic aorta, where they can induce a verminous aneurysm (Simoens et al., 1999). Thoracic aortic aneurysms and aortic ruptures are rare. However, in Friesian horses an increased incidence of aortic rupture has been reported and is most likely a genetic disease (van der Linde-Sipman et al., 1985; Ploeg et al., 2013, 2015) with rupture Ó 2016 Elsevier Ltd. All rights reserved.
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occurring consistently in the thoracic aorta near the ligamentum arteriosum and often associated with aortopulmonary fistulation (Ploeg et al., 2013). In non-Friesian horses, few thoracic aortic aneurysms have been described (Rooney et al., 1967; Holmes et al., 1973; Roby et al., 1986; Shirai et al., 1999; Okamoto et al., 2007). Breeding stallions are more often affected than mares and the aortic aneurysms and ruptures are mainly located at the base of the aortic arch at the sinuses of Valsalva (Holmes et al., 1973; Derksen et al., 1981; Roby et al., 1986; Reef et al., 1990; Lester et al., 1992). Rupture at the aortic root can result in the formation of an aortocardiac fistula (Rooney et al., 1967; Marr et al., 1998). A 7-year-old warmblood mare showed sudden onset of mild intermittent haemoptysis during a training session. Thorough clinical examination revealed no other abnormalities. Laboratory diagnostic tests, including haematological and serum biochemical examinations and coagulation tests, were performed and revealed anaemia (haematocrit 25.9%, reference interval 30e46%), hypoalbuminaemia (albumin 20.1 g/l, reference interval 25e35 g/l), neutrophilia (segmented neutrophils 10.69 109/l, reference interval 2.26e8.58 109/l) and vitamin E deficiency. Prothrombin time and activated partial thromboplastin time were normal. Endoscopic examination of the airways was performed to check for an ethmoid haematoma and to examine the guttural pouches. Both were normal, but when the trachea was visualized, blood was noticed with blood clots near the tracheal bifurcation. Unilateral pulmonary haemorrhage was suspected and treatment was started with doxycycline (10 g q24h of 75% doxycycline) and a vitamin and mineral supplement. Training of the horse was suspended. Five days later, clinical examination revealed wheezing sounds. Haematocrit and coagulation tests were re-evaluated and the haematocrit had dropped even further (23.5%) despite normal coagulation times. Endoscopic examination of the respiratory tract was repeated and showed the same findings as described previously. Treatment with clenbuterol (0.4 mg q12h) was added to the current treatment, but a few days later the horse was found dead in the stable lying in a large pool of blood and frothy sputum (Fig. 1). A full necropsy examination was performed. At the level of the brachiocephalic trunk, a 25 cm long aortic aneurysm communicating with a pseudoaneurysm (diameter 6 cm) was detected (Fig. 2). This pseudoaneurysm was surrounded by an irregular, 1.5 cm thick fibrotic wall and both the aneurysm and pseudoaneurysm contained blood clots mixed
Fig. 1. The horse was found dead in the stable with frothy sputum leaking from the nose.
with fibrin. Streptococcus equi subspecies zooepidemicus was isolated from a fibrin clot present in the aneurysm. The thoracic aorta distal to this aneurysm showed mild aneurysmal dilation with an irregular, fibrotic change to the wall and multiple mineralized intimal plaques. The pseudoaneurysm fistulated into the subpleural space and into a right bronchial branch. The right lung was severely congested and showed extensive haemorrhage. All other organs showed no obvious gross changes. Tissue samples were fixed in 4% neutral buffered formalin, processed routinely and embedded in paraffin wax. Sections (5 mm) were stained with haematoxylin and eosin (HE). Immunohistochemistry (IHC) for elastin and smooth muscle actin was performed as described by Ploeg et al. (2015). The aneurysm wall was characterized by extensive medial fibrosis with only scattered aggregated remnants of elastic fibres and smooth muscle cells. The elastic fibres showed prominent degeneration,
Fig. 2. The aortic aneurysm (*) demonstrating the site of rupture and entrance to the pseudoaneurysm (#).
Aortobronchial Fistula in a Mare
fragmentation and mineralization. This mineralization was mainly observed in the mid-medial region. There was deposition of mucoid material in the tunica media. The adventitial layer showed extensive fibrotic thickening. Multifocally, small aggregates of lymphocytes, plasma cells and macrophages were noticed in the tunica adventitia. A large number of blood vessels were present within the adventitia (neovascularization) with striking intimal proliferation. The pseudoaneurysm wall consisted of a thick layer of bundles of dense collagen fibres admixed with some fibroblasts and a small amount of adipose tissue. There were multifocal aggregates of lymphocytes, plasma cells and haemosiderin-laden macrophages. A moderate number of small to large blood vessels were also present in the wall. The thoracic aorta immediately proximal to the aneurysm showed prominent laminar medial necrosis in the mid-media, observed as a laminar band of hypereosinophilic smooth muscle cells with loss of nuclei. The thoracic aorta distal to the aneurysm showed extensive necrosis of the outer third of the media with mineralization (Fig. 3) and heterotopic bone formation (Fig. 4). Throughout the tunica media, there was extensive fibrosis with fragmentation and mineralization of elastic fibres. Large mucin deposits were noticed subintimally. This is the first report describing the gross and histological findings of aortic rupture with aortobronchial fistulation in a horse. Aortobronchial fistula is a rare but life-threatening entity in man, characterized by a communication between the aorta and a branch of the bronchial tree and developing as a consequence of processes that arise within the aorta or in the adjacent thoracic organs (Wood et al., 1984; Falode et al., 2006; Li et al., 2013). The main
Fig. 3. Mineralization of elastic fibres (arrows) in the tunica media of the thoracic aorta. Von Kossa’s stain. Bar, 100 mm.
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Fig. 4. Heterotopic bone formation (arrow) in the tunica media of the thoracic aorta. HE. Bar, 100 mm.
cause of this condition in man is a true aortic aneurysm (Wood et al., 1984; MacIntosh et al., 1998; Li et al., 2013). Common causes of aortic aneurysms are atherosclerosis, trauma, infectious diseases or genetic connective tissue disorders like Marfan and EhlerseDanlos syndromes (Massetti et al., 1997; Tsokos and Byard, 2007; Cury et al., 2013; Li et al., 2013). Aortic aneurysms with or without rupture are rare in horses (Rooney et al., 1967; Holmes et al., 1973; van der Linde-Sipman et al., 1985). To date, only a few reports describe histological findings (Rooney et al., 1967; van der Linde-Sipman et al., 1985; Marr et al., 1998; Okamoto et al., 2007) and mention aortic medial necrosis with areas of calcification (Rooney et al., 1967; van der Linde-Sipman et al., 1985; Okamoto et al., 2007). In the present case, the medial necrosis was histologically most prominent in the thoracic aorta just proximal to the aneurysm. The distal part also showed medial necrosis, but the mineralization and heterotopic bone formation were more prominent. Mineralization of the aorta has been reported sporadically in horses, mainly racehorses (Imaizumi et al., 1989; Arroyo et al., 2008), but heterotopic bone formation in the aortic wall is never mentioned. One report in horses does mention ectopic ossification with haemopoietic bone marrow in the heart valves of a horse (Matsuda et al., 2010). In man, the most common form of calcific vasculopathy is atherosclerosis (Demer and Tintut, 2008), but aortic arch calcification is also recognized in patients with oestrogen deficiency, chronic inflammation and renal disease (Demer and Tintut, 2008; Yap et al., 2016). Calcification occurs in both the intimal and medial layer and leads to vascular stiffness with reduced vascular compliance (London
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et al., 2003). This chronic degenerative process eventually results in permanent weakening and dilation of the aortic wall (Rajiah, 2013). The pathogenesis of the mineralization and heterotopic bone formation in the present case was unknown, but clinical presentation and gross examination showed no indications of renal disease or chronic inflammation. Fistulation of the aorta to other tubular organs is rare; however, in Friesian horses, fistulation between the aorta and pulmonary artery is well known and most likely occurs as a result of genetic disease. The thoracic aorta ruptures consistently just proximal to the ligamentum arteriosum, with formation of one or more pseudoaneurysms, and eventually connects to the pulmonary artery. In Friesian horses, a concurrent aneurysmal dilation of the aorta is not present, indicating a different underlying pathogenesis compared with the present case. A common cause of mainly abdominal aortic aneurysms in horses is an infestation with S. vulgaris (Simoens et al., 1999). In the present case, parasitic infestation as an underlying cause of the aneurysm appears unlikely. Deworming protocols were in order and eosinophils and giant cells did not form part of the vascular lesions. Other inflammatory processes, such as endocarditis or aortitis, were excluded based on histological findings. Bacterial culture of the aneurysmal fibrin was positive for S. equi subspecies zooepidemicus, but this is an opportunistic commensal in horses (Timoney, 2004). Furthermore, since bacterial lesions in the aorta were inapparent, this is most likely a secondary phenomenon. An underlying connective tissue disorder cannot be discounted. Marfan syndrome is an inherited disorder in fibrillin metabolism, described in cattle as well as man. Affected cattle have joint hypermobility, dolichostenomelia, ectopia lentis and aortic dilation. They often die of aortic dissection (Potter and Besser, 1994). This condition is not described in horses and, in the present case, no other compatible lesions were detected. In man, aortic aneurysm mainly occurs in the ascending segment of the thoracic aorta (Rajiah, 2013), but an aortobronchial fistula mainly involves the descending thoracic aorta and the major airways of the left lung. This is due to their close anatomical proximity (Fernandez-Gonzalez et al., 1996). In the present case, however, there was a connection with a right bronchial branch. The clinical course in people is typically characterized by recurrent haemoptysis, which was also the main clinical sign in this horse. Other symptoms in human patients may include cough, dyspnoea and chest pain (Demeter and Cordasco, 1980; MacIntosh et al., 1998; Yoo et al., 2001). The intermittent nature of the haemoptysis is explained by the thrombogenicity of the pulmonary
parenchyma. When the fistula is first established, a small amount of blood will be expectorated. The haemoptysis will stop after clot formation in the fistula. When the clot lyses or becomes dislodged, more haemoptysis ensues. This process is repeated until the fistulous opening and the haemorrhage become large enough to cause exsanguination (Graeber et al., 1973). The present case showed a similar clinical presentation and also terminated in sudden death due to massive haemoptysis. The histological findings of prominent aortic mineralization and ectopic ossification also indicate a chronic disease process. To date, this is the first report of an aortobronchial fistula in a horse or in any other animal species. The lesions were advanced and the aetiology was not established. Although in horses with intermittent hemoptysis the main differential diagnoses are ethmoid haematoma and exercise-induced pulmonary haemorrhage, clinicians should also consider aortobronchial fistulation as a possibility. Careful dissection of the upper airways and adjacent vessels is important in cases of fatal haemoptysis.
Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jcpa.2016.07. 007.
References Arroyo LG, Hayes MA, DeLay J, Rao C, Duncan B et al. (2008) Arterial calcification in race horses. Veterinary Pathology, 45, 617e625. Cury M, Zeidan F, Lobato AC (2013) Aortic disease in the young: genetic aneurysm syndromes, connective tissue disorders, and familial aortic aneurysms and dissections. International Journal of Vascular Medicine, 2013, 267215. Demer LL, Tintut Y (2008) Vascular calcification: pathobiology of a multifaceted disease. Circulation, 117, 2938e2948. Demeter SL, Cordasco EM (1980) Aortobronchial fistula: keys to successful management. Angiology, 31, 431e435. Derksen FJ, Reed SM, Hall CC (1981) Aneurysm of the aortic arch and bicarotid trunk in a horse. Journal of the American Veterinary Medical Association, 179, 692e695. Falode T, Alphonso N, Austin C, Anderson D (2006) Aortobronchial fistula: the hidden connection. Asian Cardiovascular Thoracic Annual, 14, 74e75. Fern andez-Gonz alez AL, Montero JA, Luna D, Gil O, Sanju an VM et al. (1996) Aortobronchial fistula secondary to chronic post-traumatic thoracic aneurysm. Texas Heart Institute Journal, 23, 174e177. Graeber GM, Farrell BG, Neville JF Jr., Parker FB Jr. (1973) Successful diagnosis and management of fistulas between the aorta and the tracheobronchial tree. Annals of Thoracic Surgery, 29, 555e561.
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Holmes JR, Rezakhani A, Else RW (1973) Rupture of a dissecting aortic aneurysm into the left pulmonary artery in a horse. Equine Veterinary Journal, 5, 65e70. Imaizumi K, Nakamura T, Kiryu K, Kanemaru T, Kaneko M (1989) Morphological changes of the aorta and pulmonary artery in thoroughbred racehorses. Journal of Comparative Pathology, 101, 1e9. Lester GD, Lombard CW, Ackerman N (1992) Echocardiographic detection of a dissecting aortic root aneurysm in a thoroughbred stallion. Veterinary Radiology and Ultrasound, 33, 202e205. Li M, Langlois N, Byard RW (2013) Fatal aortobronchial fistula. Journal of Forensic and Legal Medicine, 20, 395e398. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B et al. (2003) Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrology, Dialysis and Transplantation, 18, 1731e1740. MacIntosh EL, Parrott JCW, Unruh HW (1998) Fistulas between the aorta and tracheobronchial tree. Annals of Thoracic Surgery, 51, 515e519. Marr CM, Reef VB, Brazil TJ, Thomas WP, Knottenbelt DC et al. (1998) Aortocardiac fistulas in 7 horses. Veterinary Radiology and Ultrasound, 39, 22e31. Massetti M, Babatasi G, Saloux E, Bhoyroo S, Khayat A (1997) Aortopulmonary fistula: a rare event in the evolution of a dissecting aneurysm of the thoracic aorta. European Journal of Cardiothoracic Surgery, 11, 994e996. Matsuda K, Tabata S, Kawamura Y, Kurosawa T, Yoshie N et al. (2010) Ectopic ossification with haemopoietic bone marrow in the heart valves of a crossbred heavy horse. Journal of Comparative pathology, 143, 213e217. Maxie MG, Robinson WF (2015) Cardiovascular system. In: Jubb, Kennedy & Palmer’s Pathology of Domestic Animals, 5th Edit., Vol. 3, MG Maxie, Ed., Saunders, Philadelphia, pp. 8e9. Okamoto M, Kamitani M, Tunoda N, Tagami M, Nagamine N et al. (2007) Mycotic aneurysm in the aortic arch of a horse associated with invasive aspergillosis. Veterinary Record, 160, 268e270. Ploeg M, Saey V, Bruijn CM, Gr€ one A, Chiers K et al. (2013) Aortic rupture and aortopulmonary fistulation in the Friesian horse: characterization of the clinical and gross postmortem findings in 24 cases. Equine Veterinary Journal, 45, 101e106. Ploeg M, Saey V, Delesalle W, Grone A, Ducatelle R (2015) Thoracic aortic rupture and aortopulmonary fistulation in the Friesian horse: histomorphologic characterization. Veterinary Pathology, 52, 152e159. Posacioglu H, Apaydin AZ (2004) Pseudoaneurysm and aortobronchial fistula after aortic coarctation repair by
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patch aortoplasty. Texas Heart Institute Journal, 31, 319e321. Potter KA, Besser TE (1994) Cardiovascular lesions in bovine Marfan syndrome. Veterinary Pathology, 31, 501e509. Rajiah P (2013) CT and MRI in the evaluation of thoracic aortic diseases. International Journal of Vascular Medicine, 2013, 797189. Reef VB, Klumpp S, Maxson AD, Sweeney RW (1990) Echocardiographic detection of an intact aneurysm in a horse. Journal of the American Veterinary Medical Association, 15, 752e755. Roby KA, Reef VB, Shaw DP, Sweeney CR (1986) Rupture of an aortic sinus aneurysm in a 15-year-old broodmare. Journal of the American Veterinary Medical Association, 189, 305e308. Rooney JR, Prickett ME, Crowe MW (1967) Aortic ring rupture in stallions. Pathologica Veterinaria, 4, 268e274. Shirai W, Momotani E, Sato T, Kashima T, Itoi Y (1999) Dissecting aortic aneurysm in a horse. Journal of Comparative Pathology, 210, 307e311. Simoens P, Vercruysse J, De Jonghe S, Ducatelle R (1999) Thoracoabdominal aortic aneurysm in two ponies. Veterinary Record, 145, 675e676. Timoney JF (2004) The pathogenic equine streptococci. Veterinary Research, 35, 397e409. Tsokos M, Byard RW (2007) Massive, fatal aspiration of blood: not necessarily a result of trauma. American Journal of Forensic Medical Pathology, 28, 53e544. van der Linde-Sipman JS, Kroneman J, Meulenaar H, Vos JH (1985) Necrosis and rupture of the aorta and pulmonary trunk in four horses. Veterinary Pathology, 22, 51e53. Wood AE, Stevenson HM, Cleland J (1984) Aortobronchial fistula: a late complication of division of the persistent ductus arteriosus. Annals of Thoracic Surgery, 38, 402e405. Yap YS, Ting KT, Chi WC, Lin CH, Liu YC et al. (2016) Aortic arch calcification predicts patency loss of arteriovenous fistula in end-stage renal disease patients. Nature Scientific Reports, 6, 24943. Yoo J-H, Lee C-T, Shim Y-S, Chung JW, Ahn H et al. (2001) Aortobronchial fistula presenting as recurrent hemoptysis and successfully treated with an endovascular stent graft. Respiration, 68, 537e539.
May 30th, 2016 ½ Received, Accepted, July 12th, 2016
Available online at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/jcpa
SPONTANEOUSLY ARISING DISEASE
Intermittent Haemoptysis due to an Aortobronchial Fistula in a Warmblood Mare H. Versnaeyen*, V. Saey*, D. Vermeiren†, K. Chiers* and R. Ducatelle* * Department of Veterinary Pathology, Faculty of Veterinary Medicine, University of Ghent and † Veterinary Practice, Perbeemd, Sint-Lenaartseweg 67, Loenhout, Belgium
Summary A 7-year-old warmblood mare showed sudden onset of mild intermittent haemoptysis. Clinical examination revealed no significant abnormalities. Haematological examination showed mild anaemia, hypoalbuminaemia and neutrophilia. Coagulation tests were normal. Endoscopic examination revealed unilateral pulmonary haemorrhage with blood clots in the bronchi and trachea. Treatment with antibiotics was started and the horse was given stable rest. Two weeks later, the horse was found dead with blood and frothy sputum leaking from the nostrils. Post-mortem examination revealed a large thoracic aortic aneurysm communicating with a pseudoaneurysm that had formed a fistula into a right bronchial branch. Microscopical examination of the aneurysm showed extensive medial fibrosis with prominent degeneration, fragmentation and mineralization of the elastic fibres and deposition of mucoid material in the tunica media. The pseudoaneurysm was lined by collagen bundles admixed with fibroblasts and a small amount of adipose tissue. Aortobronchial fistula is a rare condition in man that is usually associated with primary aortic pathology, most often aneurysms. To the authors’ knowledge this is the first case of a fatal aortobronchial fistula in a horse or any other animal species. Ó 2016 Elsevier Ltd. All rights reserved. Keywords: aortic aneurysm; aortobronchial fistula; horse; pseudoaneurysm
Aortobronchial fistula is a rare condition characterized by the development of a communication between the aorta and a branch of the bronchial tree. This condition has only been described in man and to the best of our knowledge has never been observed in any animal species. In man, the mortality rate is 100% if left untreated (Wood et al., 1984; Fernandez-Gonzalez et al., 1996; MacIntosh et al., 1998; Posacioglu and Apaydin, 2004; Li et al., 2013). The clinical course in human patients is characterized by recurrent haemoptysis of varying severity, ranging from intermittent and minor to massive, with subsequent death. An underlying aneurysm is usually associated with this disease. An aneurysm is a localized abnormal dilation of any vessel. True aneurysms are composed of all or most layers of the intact vessel wall. False aneurysms, also called pseudoaneurysms, Correspondence to: H. Versnaeyen (e-mail: [email protected]). 0021-9975/$ - see front matter http://dx.doi.org/10.1016/j.jcpa.2016.07.007
result from rupture of an artery or aneurysm, with disruption of all three layers of the arterial wall and communication with the arterial lumen (Maxie and Robinson, 2015). As aortic aneurysms expand they exert pressure on the adjacent tracheobronchial tree with tissue necrosis and eventually breakdown of the intervening vascular and bronchial walls, allowing direct communication between the circulation and the lumen of the upper airways (Li et al., 2013). In horses, aortic aneurysms are typically located abdominally and are often associated with Strongylus vulgaris arteritis (Simoens et al., 1999). Strongyles may also move up the thoracic aorta, where they can induce a verminous aneurysm (Simoens et al., 1999). Thoracic aortic aneurysms and aortic ruptures are rare. However, in Friesian horses an increased incidence of aortic rupture has been reported and is most likely a genetic disease (van der Linde-Sipman et al., 1985; Ploeg et al., 2013, 2015) with rupture Ó 2016 Elsevier Ltd. All rights reserved.
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occurring consistently in the thoracic aorta near the ligamentum arteriosum and often associated with aortopulmonary fistulation (Ploeg et al., 2013). In non-Friesian horses, few thoracic aortic aneurysms have been described (Rooney et al., 1967; Holmes et al., 1973; Roby et al., 1986; Shirai et al., 1999; Okamoto et al., 2007). Breeding stallions are more often affected than mares and the aortic aneurysms and ruptures are mainly located at the base of the aortic arch at the sinuses of Valsalva (Holmes et al., 1973; Derksen et al., 1981; Roby et al., 1986; Reef et al., 1990; Lester et al., 1992). Rupture at the aortic root can result in the formation of an aortocardiac fistula (Rooney et al., 1967; Marr et al., 1998). A 7-year-old warmblood mare showed sudden onset of mild intermittent haemoptysis during a training session. Thorough clinical examination revealed no other abnormalities. Laboratory diagnostic tests, including haematological and serum biochemical examinations and coagulation tests, were performed and revealed anaemia (haematocrit 25.9%, reference interval 30e46%), hypoalbuminaemia (albumin 20.1 g/l, reference interval 25e35 g/l), neutrophilia (segmented neutrophils 10.69 109/l, reference interval 2.26e8.58 109/l) and vitamin E deficiency. Prothrombin time and activated partial thromboplastin time were normal. Endoscopic examination of the airways was performed to check for an ethmoid haematoma and to examine the guttural pouches. Both were normal, but when the trachea was visualized, blood was noticed with blood clots near the tracheal bifurcation. Unilateral pulmonary haemorrhage was suspected and treatment was started with doxycycline (10 g q24h of 75% doxycycline) and a vitamin and mineral supplement. Training of the horse was suspended. Five days later, clinical examination revealed wheezing sounds. Haematocrit and coagulation tests were re-evaluated and the haematocrit had dropped even further (23.5%) despite normal coagulation times. Endoscopic examination of the respiratory tract was repeated and showed the same findings as described previously. Treatment with clenbuterol (0.4 mg q12h) was added to the current treatment, but a few days later the horse was found dead in the stable lying in a large pool of blood and frothy sputum (Fig. 1). A full necropsy examination was performed. At the level of the brachiocephalic trunk, a 25 cm long aortic aneurysm communicating with a pseudoaneurysm (diameter 6 cm) was detected (Fig. 2). This pseudoaneurysm was surrounded by an irregular, 1.5 cm thick fibrotic wall and both the aneurysm and pseudoaneurysm contained blood clots mixed
Fig. 1. The horse was found dead in the stable with frothy sputum leaking from the nose.
with fibrin. Streptococcus equi subspecies zooepidemicus was isolated from a fibrin clot present in the aneurysm. The thoracic aorta distal to this aneurysm showed mild aneurysmal dilation with an irregular, fibrotic change to the wall and multiple mineralized intimal plaques. The pseudoaneurysm fistulated into the subpleural space and into a right bronchial branch. The right lung was severely congested and showed extensive haemorrhage. All other organs showed no obvious gross changes. Tissue samples were fixed in 4% neutral buffered formalin, processed routinely and embedded in paraffin wax. Sections (5 mm) were stained with haematoxylin and eosin (HE). Immunohistochemistry (IHC) for elastin and smooth muscle actin was performed as described by Ploeg et al. (2015). The aneurysm wall was characterized by extensive medial fibrosis with only scattered aggregated remnants of elastic fibres and smooth muscle cells. The elastic fibres showed prominent degeneration,
Fig. 2. The aortic aneurysm (*) demonstrating the site of rupture and entrance to the pseudoaneurysm (#).
Aortobronchial Fistula in a Mare
fragmentation and mineralization. This mineralization was mainly observed in the mid-medial region. There was deposition of mucoid material in the tunica media. The adventitial layer showed extensive fibrotic thickening. Multifocally, small aggregates of lymphocytes, plasma cells and macrophages were noticed in the tunica adventitia. A large number of blood vessels were present within the adventitia (neovascularization) with striking intimal proliferation. The pseudoaneurysm wall consisted of a thick layer of bundles of dense collagen fibres admixed with some fibroblasts and a small amount of adipose tissue. There were multifocal aggregates of lymphocytes, plasma cells and haemosiderin-laden macrophages. A moderate number of small to large blood vessels were also present in the wall. The thoracic aorta immediately proximal to the aneurysm showed prominent laminar medial necrosis in the mid-media, observed as a laminar band of hypereosinophilic smooth muscle cells with loss of nuclei. The thoracic aorta distal to the aneurysm showed extensive necrosis of the outer third of the media with mineralization (Fig. 3) and heterotopic bone formation (Fig. 4). Throughout the tunica media, there was extensive fibrosis with fragmentation and mineralization of elastic fibres. Large mucin deposits were noticed subintimally. This is the first report describing the gross and histological findings of aortic rupture with aortobronchial fistulation in a horse. Aortobronchial fistula is a rare but life-threatening entity in man, characterized by a communication between the aorta and a branch of the bronchial tree and developing as a consequence of processes that arise within the aorta or in the adjacent thoracic organs (Wood et al., 1984; Falode et al., 2006; Li et al., 2013). The main
Fig. 3. Mineralization of elastic fibres (arrows) in the tunica media of the thoracic aorta. Von Kossa’s stain. Bar, 100 mm.
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Fig. 4. Heterotopic bone formation (arrow) in the tunica media of the thoracic aorta. HE. Bar, 100 mm.
cause of this condition in man is a true aortic aneurysm (Wood et al., 1984; MacIntosh et al., 1998; Li et al., 2013). Common causes of aortic aneurysms are atherosclerosis, trauma, infectious diseases or genetic connective tissue disorders like Marfan and EhlerseDanlos syndromes (Massetti et al., 1997; Tsokos and Byard, 2007; Cury et al., 2013; Li et al., 2013). Aortic aneurysms with or without rupture are rare in horses (Rooney et al., 1967; Holmes et al., 1973; van der Linde-Sipman et al., 1985). To date, only a few reports describe histological findings (Rooney et al., 1967; van der Linde-Sipman et al., 1985; Marr et al., 1998; Okamoto et al., 2007) and mention aortic medial necrosis with areas of calcification (Rooney et al., 1967; van der Linde-Sipman et al., 1985; Okamoto et al., 2007). In the present case, the medial necrosis was histologically most prominent in the thoracic aorta just proximal to the aneurysm. The distal part also showed medial necrosis, but the mineralization and heterotopic bone formation were more prominent. Mineralization of the aorta has been reported sporadically in horses, mainly racehorses (Imaizumi et al., 1989; Arroyo et al., 2008), but heterotopic bone formation in the aortic wall is never mentioned. One report in horses does mention ectopic ossification with haemopoietic bone marrow in the heart valves of a horse (Matsuda et al., 2010). In man, the most common form of calcific vasculopathy is atherosclerosis (Demer and Tintut, 2008), but aortic arch calcification is also recognized in patients with oestrogen deficiency, chronic inflammation and renal disease (Demer and Tintut, 2008; Yap et al., 2016). Calcification occurs in both the intimal and medial layer and leads to vascular stiffness with reduced vascular compliance (London
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et al., 2003). This chronic degenerative process eventually results in permanent weakening and dilation of the aortic wall (Rajiah, 2013). The pathogenesis of the mineralization and heterotopic bone formation in the present case was unknown, but clinical presentation and gross examination showed no indications of renal disease or chronic inflammation. Fistulation of the aorta to other tubular organs is rare; however, in Friesian horses, fistulation between the aorta and pulmonary artery is well known and most likely occurs as a result of genetic disease. The thoracic aorta ruptures consistently just proximal to the ligamentum arteriosum, with formation of one or more pseudoaneurysms, and eventually connects to the pulmonary artery. In Friesian horses, a concurrent aneurysmal dilation of the aorta is not present, indicating a different underlying pathogenesis compared with the present case. A common cause of mainly abdominal aortic aneurysms in horses is an infestation with S. vulgaris (Simoens et al., 1999). In the present case, parasitic infestation as an underlying cause of the aneurysm appears unlikely. Deworming protocols were in order and eosinophils and giant cells did not form part of the vascular lesions. Other inflammatory processes, such as endocarditis or aortitis, were excluded based on histological findings. Bacterial culture of the aneurysmal fibrin was positive for S. equi subspecies zooepidemicus, but this is an opportunistic commensal in horses (Timoney, 2004). Furthermore, since bacterial lesions in the aorta were inapparent, this is most likely a secondary phenomenon. An underlying connective tissue disorder cannot be discounted. Marfan syndrome is an inherited disorder in fibrillin metabolism, described in cattle as well as man. Affected cattle have joint hypermobility, dolichostenomelia, ectopia lentis and aortic dilation. They often die of aortic dissection (Potter and Besser, 1994). This condition is not described in horses and, in the present case, no other compatible lesions were detected. In man, aortic aneurysm mainly occurs in the ascending segment of the thoracic aorta (Rajiah, 2013), but an aortobronchial fistula mainly involves the descending thoracic aorta and the major airways of the left lung. This is due to their close anatomical proximity (Fernandez-Gonzalez et al., 1996). In the present case, however, there was a connection with a right bronchial branch. The clinical course in people is typically characterized by recurrent haemoptysis, which was also the main clinical sign in this horse. Other symptoms in human patients may include cough, dyspnoea and chest pain (Demeter and Cordasco, 1980; MacIntosh et al., 1998; Yoo et al., 2001). The intermittent nature of the haemoptysis is explained by the thrombogenicity of the pulmonary
parenchyma. When the fistula is first established, a small amount of blood will be expectorated. The haemoptysis will stop after clot formation in the fistula. When the clot lyses or becomes dislodged, more haemoptysis ensues. This process is repeated until the fistulous opening and the haemorrhage become large enough to cause exsanguination (Graeber et al., 1973). The present case showed a similar clinical presentation and also terminated in sudden death due to massive haemoptysis. The histological findings of prominent aortic mineralization and ectopic ossification also indicate a chronic disease process. To date, this is the first report of an aortobronchial fistula in a horse or in any other animal species. The lesions were advanced and the aetiology was not established. Although in horses with intermittent hemoptysis the main differential diagnoses are ethmoid haematoma and exercise-induced pulmonary haemorrhage, clinicians should also consider aortobronchial fistulation as a possibility. Careful dissection of the upper airways and adjacent vessels is important in cases of fatal haemoptysis.
Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jcpa.2016.07. 007.
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May 30th, 2016 ½ Received, Accepted, July 12th, 2016