Exercise-induced pulmonary hemorrhage

Approximately 43 to 75% of horses have blood in the trachea and bronchi following a single post-race endoscopic examination.[7] In one study, all horses endoscoped on at least three separate occasions following racing had EIPH at least once.[8]

Epistaxis (blood coming from one or both nostrils) is much less common, occurring in 0.25–13% of cases.[1][9] In a survey of over 220,000 horse starts in UK Flat and National Hunt (jump) racing, 185 cases of epistaxis were identified (0.83 per 1000 starts). Similar frequencies have been reported in Japan (1.5 per 1000 starts) and South Africa (1.65 per 1000 starts), whereas a higher frequency has been reported in Korean (8.4 per 1000 starts).[10]

EIPH reduces a horse's racing performance. Severe EIPH (epistaxis) shortens a horse's racing career. Moderate to severe EIPH is associated with a worsened finishing position in a race, and finishing farther behind the winner. Horses with mild EIPH earn more prize money than those with more severe EIPH.[12] While single bouts of EIPH may not even be apparent to the rider, owner or trainer of a horse unless an endoscopic examination is undertaken, the effect on performance within a single race appears to be significant but relatively subtle.[13] In a 2005 study, horses finishing races with grade 4 EIPH were on average 6 metres behind those finishing with grade 0.[13] However, the effect of repeated bouts of EIPH that occur with daily training may lead to more significant changes and a greater degree of tissue damage over time[14] with consequent loss of lung function.

EIPH is most commonly diagnosed by endoscopic examination of the trachea and larger bronchi, with the optimal timing for endoscopy being 60–90 minutes after hard exercise.[15] This post-exercise delay allows time for blood within the lungs to travel to the trachea.[17] Blood can usually be detected in the trachea or bronchi for 1–3 days after an episode of EIPH, but may be present for up to a week.[18] The amount of blood visible in the trachea at the time of examination is most commonly graded on a scale of 0 (no blood) to 4 (airways awash with blood).[19] In some mildly-affected horses, endoscopy must be performed on multiple occasions to confirm a diagnosis of EIPH.[20]

The level of restraint required to allow endoscopy to be performed depends on the horse; a nose twitch or sedation may be required.[18]

Cytopathology (examination under a microscope) of either a tracheal wash or a bronchoalveolar lavage sample can determine whether EIPH has occurred.

1. For acute hemorrhage the number of red blood cells present can be quantified using a hemocytometer. A normal lung wash sample contains fewer than 10 red blood cells/μl of fluid. In the case of EIPH, the numbers will be several magnitudes or more higher.
2. For chronic hemorrhage the presence of high numbers of hemosiderophages, with a lot of iron inside their vesicles, indicate that hemorrhage has occurred in the lung at some time in the past. Hemosiderophages are alveolar macrophages that have ingested and digested red blood cells from previous episodes of EIPH. The end product of the digestion of the red blood cells is an iron-storage complex known as hemosiderin.[21]
   

   Schematic of the continuous hemosiderin content in alveolar macrophages stained with Perl’s Prussian blue. According to the scoring system by Doucet and Viel,[22] macrophages have to be classified into 5 discrete grades. (a) Grade 0. (b) Borderline between Grades 0 and 1. (c) Grade 1. (d) Borderline between Grades 1 and 2. (e) Grade 2. (f) Borderline between Grades 2 and 3. (g) Grade 3. (h) Borderline between Grades 3 and 4. (i) Grade 4.[21]

Bronchoalveolar lavage (BAL) is a procedure whereby a small volume of fluid is put into the airways in order sample the cells and fluids of the alveoli and epithelium of the bronchi.[23] BAL may be performed using a BAL tube, which allows fluid to be added to and removed from the bronchi, or may be performed during endoscopy, if the endoscope has an irrigation channel.[24] To perform BAL, the horse is usually sedated, and local anaesthetic is usually instilled into the airways to reduce coughing.[24]

BAL is less useful when severe hemorrhage has occurred. BAL results only reflect the situation in the localized region of the lung which has been lavaged, and may not be representative of the whole lung.[24] The fluid obtained by BAL is submitted for cytological examination.

Imaging the lungs by taking a radiograph (x-ray) of the chest cannot be used to diagnose EIPH, as the lungs of affected and unaffected horses share the same characteristics.[20]

Scintigraphy of the lungs may detect moderate to severe alterations in the perfusion and possibly ventilation of the dorso-caudal lung.[25] The use of radio-labelled red blood cells and scintigraphy to localise and or quantify hemorrhage is not useful due to general sequestration of labeled RBC by the lung, even in the absence of hemorrhage.[26]

EIPH seldom causes the death of a horse, but if an affected horse dies and undergoes a post-mortem examination, repeated episodes of EIPH will have caused a characteristic blue-gray-brown staining in the lungs.[27] The staining is due to the presence of hemosiderin. The staining is usually most intense in the dorso-caudal region of the left and right diaphragmatic lobes which often progresses cranioventral with repetitive damage. There are often distinct borders between healthy lung tissue and those parts of the lungs that have been affected by EIPH. Other histopathologic findings include fibrosis, bronchial artery neovascularization, venous remodeling, bronchiolitis, hemosiderin accumulation, increased tissue cellularity (i.e. hemosiderophages), multifocal areas of inflammation, and increased thickness of vascular and airway walls.

The most widely accepted theory is that high transmural pressures lead to pulmonary capillary stress failure. There may be contributions from the bronchial circulation. Pulmonary capillary transmural pressure is determined by pulmonary capillary pressure and airway pressure. The horse has very high pulmonary vascular pressures during intense exercise, exceeding 100 mmHg in the pulmonary artery during intense exercise. During expiration the high positive pressures in the pulmonary blood vessels pushing out are opposed by high positive airway pressures pushing back and this does not place undue stress on the thin blood vessel walls. During inspiration, the high positive pressures in the pulmonary blood vessels pushing out are met by negative pressures distending the blood vessel and placing increased stress on the walls. Studies in vitro show that significant disruption of the pulmonary capillaries occurs at pressures of approximately 80 mmHg. In vivo, significant EIPH occurs above a mean pulmonary artery pressure of around 80–95 mmHg.[28][29] On the basis of this theory, any factor or disease that would increase pulmonary vascular pressures (e.g. hypervolaemia) or increase the magnitude of the negative pressures in the lung during inspiration (e.g. dynamic upper airway obstruction) would increase the severity of EIPH; however neither experimentally induced laryngeal hemiplegia nor dorsal displacement of the soft palate increase pulmonary capillary transmural pressure.[30][31] Furthermore, the magnitude of exercise-induced pulmonary arterial, capillary and venous hypertension is reportedly similar in horses either with or without EIPH.

This theory is based on the fact that, during galloping, the absence of any bone attachment of the forelegs to the spine in the horse causes the shoulder to compress the cranial rib cage.[32] The compression of the chest initiates a pressure wave of compression and expansion which spreads outwards. However, due to the shape of the lung and reflections off the chest wall, the wave of expansion and compression becomes focussed and amplified in the dorso-caudal lung.[33] The alternate expansion and compression at the microscopic level in adjacent areas of lung tissue creates shear stress and capillary disruption. The theory predicts that hemorrhage would be more severe on hard track surfaces, but it does not explain why EIPH can occur in horses during swimming exercise.

This theory proposes how high pulmonary venous pressures may lead to the capillary rupture and the tissue changes observed in EIPH.[14] Regional veno-occlusive remodeling, especially within the caudodorsal lung fields, contributes to the pathogenesis of EIPH, with the venous remodeling leading to regional vascular congestion and hemorrhage, hemosiderin accumulation, fibrosis, and bronchial angiogenesis.

While all horses undertaking intense exercise experience some degree of EIPH, some horses consistently experience greater haemorrhage and other horses experience isolated episodes of increased EIPH. In the case of horses that consistently demonstrate greater severity of EIPH this is most likely due to congenital factors, such as very high pulmonary vascular pressures. In horses that experience isolated episodes of increased severity of EIPH, possible contributing factors may include, amongst others, pulmonary infection or atrial fibrillation, inflammation, longer distances, longer duration of exercise, hard surfaces, steeplechasing/hurdling, increased length of career, breed (i.e. Thoroughbred greater than Standardbred), time in training/racing, genetics, and cold temperatures.