A 5-year-old, 515-kg, Thoroughbred-Warmblood cross gelding was referred to the Cornell University Hospital for Animals for evaluation of hard swellings on the long bones of the limbs and intermittent fever. The horse had a 6-month history of weight loss with good appetite. Hard swellings were first noted medially on the distal radii and distal tibias 2 weeks before presentation; swellings were later noted as well on the proximal metatarsi and left metacarpus. Intermittent fevers during that time ranged from 101.7 to 104.7°F. No clinical signs of respiratory disease were noted. Before referral to the Cornell University Hospital for Large Animals, the horse was treated with flunixin meglumine (500 mg IV) on 4 occasions to control the fever and trimethoprim-sulfa (30 mg/kg PO q24h for 7 days) with no apparent improvement. Two days before presentation, the horse was treated with topical atropine for blepharospasm and miosis of the left eye.
On presentation, the horse was bright, alert, and afebrile, with a normal rectal temperature (100.6°F), heart (42 beats/min), and respiration (24 breaths/min) rates. The body condition score was 3/9. The pupils were mildly anisocoric with the left slightly more dilated than the right, which was assumed related to previous atropine treatment. Mild circumlimbal peripheral corneal edema was present in both eyes with no evidence of uveitis. Thoracic auscultation was normal at rest although mildly increased bronchovesicular sounds were heard over the right hemithorax compared with the left after more forced effort (rebreathing into a large plastic bag). No cough was elicited during the exam, on palpation of the trachea, or during exercise, and nasal discharge was absent. Mandibular lymph nodes were not enlarged. On palpation of the limbs, marked enlargement of the distal radial metaphyses, with lesser enlargement of the mid-left metacarpus, distal tibial metaphyses, and metatarsal metaphyses and diaphyses, was noted. The bony enlargements were most prominent medially on the limbs. There was mild pitting edema along the metatarsal area but none in the forelegs. The horse was stiff walking out of the stall but did not show overt lameness at a trot and seemed to have reference range of motion in all joints.
Radiographs of the limbs showed moderate well mineralized, smooth to palisading periosteal proliferation circumferentially around the distal diaphyses of the radii, tibias, and proximal metatarsi (Fig 1). The articular surfaces and cuboidal bones were unaffected. Small osteophytes were noted in the left carpo-metacarpal joint. Based on the clinical exam and symmetrical periostitis of all 4 limbs, a diagnosis of hypertrophic osteopathy (HO) was made for the skeletal lesions.
Thoracic radiographs and thoracic and abdominal ultrasound were pursued to determine an underlying cause for the HO. Radiographs showed a 6–7 cm diameter, ill-defined, soft-tissue opacity in the thorax, ventral to the caudal vena cava. Thoracic ultrasound revealed four, 3–5 cm long × 1.5 cm deep, hypoechoic nodules on the surface of the right lung from the 9th rib cranially to the 6th rib (Fig 2a). The left hemithorax had superficial hyperechoic areas with mild comet tail artifacts indicating pleural roughening and a few small hypoechoic areas (<1 cm3). Bilaterally mild pleural effusion was seen cranioventrally.
CBC showed mild anemia (hematocrit [Hct] 27% [reference range, 34–46%]), high normal mature neutrophils (6.0 thou/μL [reference range, 2.7–6.6 thou/μL]), and mild lymphopenia (1.1 thou/μL [reference range, 1.2–4.9 thou/μL]). Serum biochemistry showed a borderline hypoalbuminemia (2.8 g/dL [reference range, 2.8–3.8 g/dL]), hyperglobulinemia (4.5 g/dL [reference range, 2.4–4.4 g/dL]), and hyperfibrinogenemia (600 mg/dL [reference range, 0–200 mg/dL]). Arterial blood gas was analyzed after 10 minutes of trot to further evaluate the extent of respiratory disease and was within normal limits.
Transtracheal wash was performed and cytologic exam showed moderate mixed, predominantly histiocytic inflammation, with large amounts of mucus. The cells were 60% macrophages, 37% mildly degenerate neutrophils, with occasional small lymphocytes. Pleural fluid was collected from the right thorax and laboratory analysis of the fluid was reported to be an exudative effusion with marked suppurative inflammation (total protein 5.3 g/dL, nucleated cell count 58.9 thou/μL, 84% nondegenerate neutrophils). Neither sample had microscopic evidence of bacteria or neoplastic cells and both were negative on aerobic and anaerobic cultures. An impression smear of a Tru-Cuta needle biopsy of the largest nodule on the right hemithorax showed well-differentiated respiratory epithelial cells with a few cuboidal forms. Low numbers of inflammatory cells included macrophages and fewer small lymphocytes, nondegenerate neutrophils, and plasma cells. Low numbers of mast cells and spindle cells were also seen. Histopathology of the lung biopsy specimen showed moderate, locally extensive, fibrosis with mild lymphoplasmacytic infiltrates and edema (Fig 3a,b). No intranuclear inclusion bodies were seen. Samples of the transtracheal wash fluid and formalin-fixed, paraffin-embedded lung biopsy specimen tissue were both negative for equine herpesvirus 5 (EHV-5) by polymerase chain reaction (PCR performed by Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI). Based on the multinodular ultrasound findings of the lung, histologic evidence of pulmonary fibrosis, and hematological changes (anemia, mature neutrophilia, lymphopenia, hyperfibrinogenemia, hypoalbuminemia), in addition to clinical signs (weight loss, fever), a presumptive diagnosis of equine multinodular pulmonary fibrosis (EMPF) was made.
The horse remained febrile (up to 104.5°F) during the 1st week of hospitalization and was treated on 3 occasions with flunixin meglumine (1 mg/kg IV). After all laboratory results were known, the horse was started on a tapering course of dexamethasone starting at 0.1 mg/kg IV every 24 hours, decreasing by 20% every 4 days for a total treatment course of 40 days. Flunixin meglumine treatment was discontinued. Because the EHV-5 PCR was negative, no antiviral therapy was used. Omeprazole (1 mg/kg PO q24h) was administered for the first 3 weeks as a preventative treatment for gastric ulceration.
The horse became afebrile within 36 hours of initiating dexamethasone treatments. Daily temperatures were taken and the horse remained afebrile during the entire course of therapy and for at least 2 weeks after corticosteroids were discontinued. After 30 days of treatment, recheck ultrasound showed marked decrease in size and number of the thoracic lesions. At 45 days, the largest initial nodule (located by a scar on the skin from the previous biopsy specimen) was reduced to <1 cm (Fig 2b) and other nodules were reduced to mild pleural roughening. Recheck blood analysis showed that the fibrinogen, globulins, Hct, and lymphocytes had normalized. The albumin had decreased slightly to 2.7 g/dL (reference range, 2.8–3.8 g/dL). During the treatment course, the horse had recurrent episodes of keratitis, conjunctivitis, and blepharospasm of the left eye. A complete ophthalmic examination was again performed at 45 days and was normal, with no signs of active or previous uveal disease (no miosis, aqueous flare, iris surface alteration, etc.). Viral isolation on conjunctival scrapings taken at that time failed to grow EHV-1 or EHV-5, although treatment with the topical antiviral cidofovir (q12h) was temporally associated with resolution of the ocular disease within 2 weeks. Five months after hospital admission the horse appeared clinically normal other than the remaining bony swelling which had not changed in size and was being used successfully as a low jumper. EMPF is a recently recognized interstitial lung disease of horses. It was first described in 2007 by Williams and colleagues based on the nodular pattern of lesions as distinct from the diffuse interstitial pattern in previously described fibrosing lung diseases of horses. Williams et al1 also demonstrated an association with EHV-5, a gammaherpesvirus of the domestic horse. Since that report, clinical cases have been diagnosed antemortem by a combination of findings including a history of chronic weight loss and intermittent fevers with or without respiratory signs, a nodular interstitial pattern on radiographs, hypoechoic nodules at the pleural surface on thoracic ultrasound, nonseptic but inflammatory transtracheal wash cytologic findings, lung biopsy specimen showing interstitial fibrosis with preservation of alveolar-like architecture, and EHV-5 PCR of bronchoalveolar lavage fluid or lung biopsy specimens or both.2–4 The patterns of anemia, hypoalbuminemia, mature neutrophilia, lymphopenia, and hyperfibrinogenemia are frequent findings in horses with EMPF, although the diagnostic value of this CBC pattern is yet to be validated.2–3
In the case presented here, a presumptive diagnosis of EMPF was made despite failure to identify EHV-5 by PCR. All previously reported cases of EMPF detected EHV-5 by PCR of bronchoalveolar lavage fluid or lung tissue, especially from postmortem samples.1–4 It is possible that performing a bronchoalveolar lavage or multiple lung biopsy specimens may have enhanced our chances of finding EHV-5. In a study to determine the prevalence of the equine alpha- and gamma-herpesviruses in horses with poor performance because of presumptive respiratory disease, the transtracheal wash was nearly as sensitive as was bronchoalveolar lavage in detecting EHV-5 prevalence in the clinically abnormal group.5 No study comparing the 2 tests in horses with EMPF has been performed to date. Also, Koch's postulates have not yet been fulfilled to prove that EHV-5 is the cause of EMPF, and to this date it remains only an association between EMPF and EHV-5. Therefore, it was considered reasonable to accept the diagnosis of EMPF without confirmation of the viral component. It is also possibly that in spite of the histologic diagnosis of pulmonary fibrosis and clinical signs, hematology findings, and ultrasound imaging of the lungs being identical to that described for EMPF that this horse had a disorder other than EMPF. The failure to find EHV-5 in the lung biopsy specimen, the small but abnormal amount of inflammatory pleural fluid, and the absence of neutrophils in the alveolar lumen of the biopsy specimen are all different from what has been reported for most EMPF cases.1–4 The excellent clinical response and apparent clinical recovery associated with corticosteroid treatment in this horse have been reported previously in 2 horses with EMPF, although those horse were treated with both corticosteroids and acyclovir.2
HO is a syndrome characterized by periosteal proliferation on the cortices of the long bones. The syndrome is classically described as secondary to space-occupying lesions in the thorax but can be idiopathic or associated with extrathoracic disease as well.6 HO is most commonly reported in people and dogs and is rare in horses. In horses, documented intrathoracic causes of HO are pulmonary abscesses, pulmonary neoplasia, granulomatous pneumonia, and rib fracture with pleural adhesions.6–9
Various pathophysiologic mechanisms for the development of HO have been described, all mediated by increased vascularity to the periosteum. Elaboration of hormonal factors by the primary lesion, chronic periosteal hypoxia, and afferent parasympathetic stimulation are the leading theories.10 In the veterinary literature, the neural theory of vagal stimulation is popular despite more recent work in the human medical field. Some of the evidence for the neural theory lies in the work of Flavell,11 who caused resolution of HO without treatment of the pulmonary disease by performing a vagotomy. Also, the causes of HO often affect the periphery of the lung, suggesting that pleural or subpleural vagal afferent fibers are involved.12 Nodules associated with EMPF are throughout the lung, but are often at the pleural surface, as seen on ultrasonographic examination, making vagal stimulation a potential mechanism of development of HO in this case. In the recent human literature, however, there is growing support for an endocrine mechanism involving a variety of hormones including local or systemic production of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), prostaglandin E2, and growth hormone releasing hormone. Large megakaryocytes are normally fractured in the pulmonary vascular bed, but pulmonary diseases that result in microvascular shunting may allow large megakaryocytes to reach systemic circulation. This can cause platelet clumping in the capillaries of the periosteum. The platelets release vasoactive substances in response to local hypoxia from blocked capillaries and the local VEGF and PDGF induce vascular proliferation, periostitis, and edema.13–15 The development of fibrosis in idiopathic pulmonary fibrosis in people is also partially mediated by PDGF.16 This suggests an alternate mechanism whereby EMPF could cause HO by systemic PDGF or VEGF increase, platelet alteration and microvascular clumping, and local autocrine responses in the periosteum. Whether EMPF caused HO by either of these proposed mechanisms, it is somewhat surprising that no previous cases of HO have been reported with EMPF.
Ocular disease concurrent with EMPF has been reported in one other case in Germany, where a Warmblood gelding presented with presumed viral keratitis and EMPF.3 EHV-2 and EHV-5 have been recovered from conjunctival or corneal swabs of horses with suspected viral keratitis or keratoconjuctivitis with clinical response to antiviral therapy in some cases.17,18 Although conjunctival viral cultures were negative, the seemingly positive response to antiviral therapy suggests that the ocular disease in this case could have been a viral keratitis. The potential for EHV-5 to cause ocular disease needs further investigation.
The prognosis for the horse in this case was complicated by the combination of disorders with which it presented. Because HO is often secondary to a serious or fatal underlying condition, it is generally considered to have a poor prognosis. One report of 24 cases shows that 71% of horses diagnosed with HO were euthanized because of progression of the HO or failure to control the underlying disease.7 Where the primary condition could be identified and treated, though, the condition has the potential to improve and even be cured over a period of months.6,8,9 The prognosis for HO also depends on the stage at which it is recognized. Horses with severe HO limiting the range of motion in their joints are more likely to be euthanized because of lameness or persistent inappetance than are milder cases.
Prognostic indicators for EMPF are not fully described, but it appears that persistent fevers despite therapy, secondary bacterial pneumonia, and pulmonary artery dilatation on echocardiogram (suggesting pulmonary hypertension) are all associated with a poor prognosis, whereas resolution of fever with treatment, weight gain, use of corticosteroids in the therapeutic regimen, and improvement of thoracic radiographs and ultrasound are all positive prognostic indicators.1–3 Because the syndrome is so recently recognized, and because some animals respond well to therapy, Wong et al2 proposed that horses diagnosed with EMPF should be given a minimum of 6 weeks of corticosteroid with or without antiviral therapy to determine if they will respond before deciding to euthanize.
This case is unique as the 1st report of HO in a horse with nodular pulmonary fibrosis and clinical findings similar to EMPF, and in the rapid positive pulmonary response to corticosteroid therapy.