1 1 Ophthalmologic findings associated with Rhodococcus equi 2 bronchopneumonia in foals 3 Iciar Tarancón DVM*, Marta Leiva Dipl ECVO, PhD, DVM †, Eduard Jose-Cunilleras Dipl 4 ACVIM, PhD, DVM*, José Ríos MSc +, Teresa Peña Dipl ECVO, PhD, DVM† 5 *Servei de Medicina Interna Equina, Unitat Equina-Fundació Hospital Clínic Veterinari, and 6 Departament de Medicina i Cirurgia Animal, Facultat de Veterinària, Universitat Autònoma de 7 Barcelona, Barcelona, Spain, †Servei d’Oftalmologia de la Fundació Hospital Clínic Veterinari, 8 Facultat de Veterinària, Universitat Autònoma de Barcelona, Bellaterra Barcelona, Spain; and 9 Departament de Medicina i Cirurgia Animals, Facultat de Veterinària, Universitat Autònoma de 10 Barcelona, Bellaterra, Barcelona, Spain, +Medical Statistics Core Facility, Institut 11 d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Hospital Clinic, Barcelona, 12 Spain. Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona 13 CORRESPONDING AUTHOR: 14 Dr. Marta Leiva 15 Postal address: Departament de Medicina i Cirurgia Animals, Facultat de Veterinària, 16 Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain. 17 Telephone: +34935811387. Fax: +34 93 581 3428 18 E-mail: marta.leiva@uab.cat 19 20 RUNNING TITLE: Ocular findings associated with R equi in foals 21 2 22 Abstract 23 Objective: To describe ocular findings associated with Rhodococcus equi bronchopneumonia in 24 foals, and to determine whether severity of the ocular lesions is related with outcome. Animals 25 studied: Foals diagnosed with R. equi infection at the VTH-UAB from January 2002 to December 26 2017. Procedure: Rhodococcus equi infection was diagnosed by means of clinical signs, 27 radiographic/ultrasonographic findings, and/or positive culture. In all the foals, a complete 28 ophthalmic examination by a boarded ophthalmologist was performed and ocular signs were 29 recorded and graded (0-4). Results: Thirty-nine foals were included in the study, from which 12 30 showed signs of bilateral anterior uveitis (30.8%). Among these, 3 foals were classified as mildly 31 uveitis-affected (MUA:7.7%) and 9 as severely uveitis-affected (SUA:23.1%). Five SUA foals 32 showed green aqueous flare (5/9;55.5%). Despite the systemic treatment, 9/39 sick foals died 33 (23.1%), being the fatality rate different between groups: SUA (4/9;44.4%), MUA (0/3; 0%) and 34 non-uveitis-affected foals (5/27;18.5%). Among SUA foals, only one with green aqueous flare 35 died (1/5;20%). Conclusion: Bilateral anterior uveitis is highly prevalent in foals with 36 Rhodococcus equi pneumonia (30.8%). The severity of anterior uveitis might be considered a 37 non-survival prognostic factor and, until proven otherwise, green aqueous flare could be taken as 38 a strongly suggestive ocular sign of the disease. Findings of this study remark the clinical 39 relevance of performing a complete ophthalmic examination in sick foals, in order to help in the 40 diagnosis and prognosis of uveal diseases, as well as to guarantee visual soundness. 41 Key words: green aqueous flare, prognosis, uveitis, eye, horse 42 43 44 3 45 INTRODUCTION 46 Ocular involvement in systemic diseases of horses is common; however, unless ophthalmic 47 examination is used as a first-approach diagnostic tool, some eye conditions may go unnoticed. 48 Detection and assessment of ocular abnormalities during investigation of horses with systemic 49 disease may provide valuable information on the differential diagnoses, treatment options and 50 prognosis of systemic disorders. Furthermore, timely recognition of ocular manifestations of 51 systemic diseases will permit targeted ophthalmic treatment with potential benefits to limiting 52 ocular pathology and vision loss.1-2 Unfortunately, ocular examination is nowadays greatly 53 underused in the diagnosis of systemic diseases in the horse.1 54 Reports on ocular manifestations of systemic diseases in foals are few, including neonatal 55 septicemia3, strangles (Streptococcus equi infection),4,5 adenoviral infection,6 equine viral 56 arteritis,7 equine herpesvirus-1 infection (EHV-1)8 and Rhodococcus equi (R. equi).9-15 To the best 57 of our knowledge, no pathognomonic ocular signs have been described to date for any systemic 58 disease in foals, being impossible to issue the etiologic diagnosis based only on ocular findings. 59 Rhodococcus equi bronchopneumonia is a well-recognized cause of morbidity and death in foals 60 aged 3 weeks to 6 months.7 R. equi is a Gram positive facultative intracellular bacterium, 61 ubiquitous in the horse environment and resistant to most disinfectants and dry conditions. This 62 microorganism induces mainly granulomatous bronchopneumonia, but also other extrapulmonary 63 disorders (EPDs), such as abdominal (ulcerative enterotyphlocolitis, intra-abdominal abscesses, 64 intra-abdominal lymphadenitis, peritonitis, pyogranulomatous lesions in liver and kidney), 65 musculoskeletal (septic arthritis, non-septic polysinovitis, osteomyelitis, myositis), hematologic 66 (immune-mediated hemolytic anemia), neurologic (intracranial abscesses, meningitis), 67 dermatologic (cellulitis, subcutaneous abscesses), and ocular.9-15 Unfortunately, up to date, 4 68 ophthalmologic lesions associated with R. equi infection have not been widely described, being 69 limited to anecdotal case reports,10,13-15 a consensus statement of the American College of 70 Veterinary Internal Medicine,11 a retrospective study focused on EPDs9 and one review paper on 71 general clinical signs.16 To the authors´ knowledge, there are no published studies describing in 72 detail complete ophthalmic examination´s findings in foals with R. equi bronchopneumonia. 73 The purpose of the present retrospective clinical study was to further characterize ocular 74 inflammatory findings in foals with R. equi bronchopneumonia, when examined by boarded 75 ophthalmologists, and to determine whether the degree of uveal inflammation is related to 76 outcome. 77 MATERIAL AND METHODS 78 Case selection 79 The medical database of the Veterinary Teaching Hospital of the Universitat Autònoma de 80 Barcelona (VTH-UAB) was reviewed to identify foals diagnosed of Rhodococcus equi 81 bronchopneumonia that underwent a complete ophthalmic examination, between January 2002 82 and December 2017. Patients lacking a fundus examination were excluded unless this was 83 impaired due to the presence of severe anterior segment inflammation. 84 Medical records review 85 Data extracted from medical records included clinical history, reason/s for initial evaluation at the 86 hospital, signalment, complete ophthalmic examination findings, bloodwork, complementary 87 imaging tests (radiography or ultrasonography) and microbiologic culture, when available. 88 For the purpose of this study, the diagnosis of R. equi infection was defined as a foal aged 3 weeks 5 89 to 6 months that met at least two of the following criteria: (1) clinical signs consistent with 90 pneumonia (temperature >39.5°C, a respiratory rate >80/minute, coughing, purulent nasal 91 discharge, abnormal lung sounds), (2) white blood cell count >13.0×109/L, (3) radiographic or 92 ultrasonography evidence of bronchopneumonia (where abscesses were defined as focal 93 hypoechoic areas of consolidation with a diameter ≥1.0 cm), and (4) cytological identification of 94 gram-positive coccobacilli in, or isolation of R. equi by microbiologic culture from an abscess or 95 tracheobronchial aspirate (TBA).9,17 96 Complete ophthalmic examination, clinical signs and foals’ classification 97 In all the foals, complete ophthalmic examination was performed in dim light conditions within 98 24 hours after admission. Menace response, dazzle reflex, palpebral reflex, and pupillary light 99 reflexes were evaluated in every foal. Diffuse transillumination and slit lamp biomicroscopic 100 examination (Kowa SL-15, Kowa Company Ltd., Tokyo, Japan) were completed and findings 101 recorded. Tonometry was performed by applanation (Tonopen XL®, Mentor, Norwell, MA, USA) 102 or rebound (TonoVet®, Icare Finland Oy, Helsinki, Finland) tonometers, followed by the 103 application of one drop of tropicamide 2% (Colircusí tropicamida, Alcon Laboratories, Masnou, 104 España) and indirect ophthalmoscopy (Heine Omega 500, Heine, Herrsching, Germany). Direct 105 ophthalmoscopy and fluorescein stain were performed when needed. 106 Ocular signs were graded as follows: absent (grade 0), mild (grade 1), moderate (grade 2), severe 107 (grade 3) and very severe (grade 4). Exudative anterior uveitis was defined as the presence of 108 aqueous flare, fibrin, hypopion and/or hyphema. Other minor ocular signs, such as corneal edema, 109 decreased intraocular pressure, miosis, keratic precipitates and synechia, were also considered and 110 classified. 111 Based on the presence and severity of the clinical signs shown, foals were then grouped as 6 112 severely uveitis-affected (SUA), mildly uveitis-affected (MUA) or non-uveitis-affected foals. 113 Horses were included in the SUA group when the degree of aqueous flare was 3 or 4, in the MUA 114 group when the degree of aqueous flare was 1 or 2, and in the non-uveitis-affected group when 115 no signs of anterior uveitis were seen. 116 Treatment and outcome 117 In addition to the appropriate systemic antimicrobial treatment [combination of a macrolide 118 (erythromycin, azithromycin or clarithromycin) and rifampin, from 3-12 weeks] and ancillary 119 therapies (nonsteroidal anti-inflammatory drugs, provision of adequate nutrition and fluid therapy, 120 oxygen therapy, bronchodilators…), topical treatment for ocular disease was also administered, 121 when needed. Foals with anterior uveitis were treated with topical dexamethasone (4-6 times/day; 122 Maxidex®, Alcon laboratorios, El Masnou, Barcelona, Spain), tropicamide (2-3 times/day; 123 Colircusí tropicamida®, Alcon Laboratorios, El Masnou, Barcelona, Spain) and artificial tears (4- 124 6 times/day; Viscotears®; Bausch & Lomb, Alcobendas, Madrid, Spain). 125 Complete ophthalmic examinations were performed daily until foals were discharged, humanely 126 euthanized or died due to systemic complications. General and ocular outcomes were recorded. 127 Poor outcome was considered when foals died or were humanely euthanized due to systemic 128 complications of the disease. Eyes were considered as visual when a positive menace response 129 and normal photopic/scotopic maze tests were present. 130 Statistical analysis 131 Descriptive statistics was performed using SPSS 22.0 (SPSS ®, Chicago, IL, USA). Quantitative 132 variables were described with the mean, minimum, and maximum values, and qualitative 133 variables with the number of animals or eyes, and percentages. 7 134 RESULTS 135 Animals 136 During the study period, a total of 44 foals were diagnosed with R. equi bronchopneumonia, but 137 only 39 met the inclusion criteria. There were 19 fillies and 20 colts of a mean age of 3 months, 138 ranging from 1 to 5 months. Andalusian horses were overrepresented (n=32/39;82.1%). 139 Rhodococcus equi bronchopneumonia was diagnosed by means of clinical signs (39/39;100%), 140 ultrasonography findings (24/39;61.5%), radiographic findings (13/39;33.3%) or a positive 141 culture in abscess or TBA (6/39;15.4%). 142 Ophthalmic findings and foal classification 143 Bilateral anterior uveitis was present in 12 foals (12/39;30.8%) (Table 1). The condition was 144 exudative in all the animals, being graded as mild in 3 foals (MUA foals 3/39;7.7%) and severe 145 in 9 (SUA foals 9/39;23.1%). In the SUA group (n=9), all the very severely affected foals (5/9) 146 depicted a marked green color of the anterior chamber aqueous flare (5/39;12.8%). Apart from 147 aqueous flare and the fibrin clots [bilaterally observed in the anterior chamber of 3 SUA foals 148 (3/39;7.7%)] there were no other specific signs of anterior uveitis (hyphema, hypopion, keratic 149 precipitates…). Posterior segment examination was precluded in all the SUA foals (9/39;23.1%), 150 in which ocular ultrasonography ruled out severe posterior segment affection. Fundus 151 examination was physiologic in all the MUA foals, showing bilateral peripapillary chorioretinal 152 inflammation in just one non-uveitis-affected foal. 153 Treatment and outcome 154 Systemic antibiotic medication was administered in all the sick foals and topical ocular medication 155 in foals affected with uveitis (12/39;30.8%), being drops frequency directly associated to uveitis 156 severity. Despite the systemic treatment, 9 out of the 39 sick foals included in the study died or 8 157 were humanely euthanized (9/39;23.1%) (Table 1). The case fatality rate differed significantly 158 between groups, being 18.5% in non-uveitis-affected foals (5/27) and 33.3% in the uveitis- 159 affected foals (4/12). Additionally, all the uveitis-affected foals that died were from the SUA 160 group (4/9;44.4%), while all the foals from the MUA group had good outcome (0/3;0%). The 161 outcome was very similar for foals with green and non-green aqueous flares, showing incidences 162 of 1/4 (20%) and 3/8 (37.5%), respectively. No ocular sequels were observed at discharge in SUA 163 (5/9;55.6%) or MUA (3/3;100%) foals, being all the eyes visual. 164 DISCUSSION 165 Ocular signs of systemic diseases have been rarely reported in foals.3-15 Rhodococcus equi 166 bronchopneumonia has been sporadically associated to ocular signs in foals,10,12-15 but no detailed 167 description of the ocular findings induced by R. equi infection has been reported. Although the 168 presence of uveitis is repeatedly named as extrapulmonary disorder (EPD) associated with R. equi, 169 this is the first study describing that severe anterior uveitis is highly prevalent in foals affected by 170 R. equi infection, characterizing its ocular findings, and suggesting that the severity of uveitis may 171 be considered as a non-survival prognosis factor in sick foals. 172 Rhodococcus equi infection in foals has been sporadically associated with ocular findings such as 173 anterior uveitis, panophthalmitis and keratouveitis, being anterior uveal affection the most 174 common ocular diagnosis.9,10,13-15 In a retrospective study on EPDs in 150 foals with R. equi 175 infection, an incidence of 11% was observed for anterior uveitis, placing iridocyclitis as the 176 seventh most common EPD, following diarrhea (33%), immune-mediated polysinovitis (25%), 177 ulcerative enterotyphlocolitis (21%), intra-abdominal abscesses (17%) and abdominal 178 lymphadenitis (17%).12 Despite both studies being performed in veterinary hospitals with 9 179 theoretically similar caseload, the incidence of uveitis in our study was significantly higher 180 (30.8% vs. 11%). This numeric discrepancy could be associated to the fact that in the present 181 study a routine complete eye exam was performed in all the sick foals within 24 hours after 182 admission, whereas in Reuss et al. study, no information was given in regards to this aspect, reason 183 why some cases may have gone unnoticed. The present findings suggest a more important clinical 184 role of uveitis in EPDs of foals with R. equi infection. Thus, ophthalmic examination is strongly 185 recommended in foals with a clinical presentation compatible with R. equi infection. 186 Ocular signs in sick foals can be unilateral or bilateral.3,10,12-15 Among all the uveitis-affected foals 187 of the study, no unilateral cases were diagnosed, showing all the foals a symmetrical presentation. 188 In all cases, uveitis was characterized by different degrees of aqueous flare, evaluated by means 189 of slit-lamp biomicroscopy. Traditionally, clinical assessment of the aqueous flare has been 190 successfully performed evaluating the refraction of a focus light when passing the anterior 191 chamber. This somehow subjective method of classification has been taught from mentors to 192 residents, reaching a uniform grading scale all over the world. Nevertheless, aqueous flare 193 evaluation can be more objectively performed by using a flare meter, which allows both, 194 determination of the flare and the number of cells present in the aqueous of the anterior chamber.18 195 Unfortunately, the diagnostic tool is non-portable and its price does not justify its use in a 196 veterinary hospital. In the present population, the biomicroscopic aqueous flare evaluation 197 depicted that the incidence of severe uveitis was significantly higher (23.1%) than mild-moderate 198 uveitis (7.7%). This finding is not surprising given the importance of the vascular spread in the 199 pathogenesis of R. equi dissemination7 and the already known weakness of the equine blood- 200 aqueous barrier (BAB).19,20 Among the SUA foals (n=9), 3 showed important amounts of fibrin 201 in the anterior chamber of both eyes (OU). The high capacity for fibrin production in foals is 10 202 already known, which in severe cases can even fill the complete anterior chamber.21,22 If not 203 treated, fibrin can induce corneal or lens sequelae, inducing different degrees of hemeralopia or 204 even blindness. Conversely to previous reports,10,12,15 no cases of hyphema, hypopion or keratic 205 precipitates, were observed in the present study. 206 To the authors´ knowledge there are no pathognomonic or indicative ocular signs reported for R. 207 equi infection. Because of the necessity of early diagnosis and treatment of R. equi 208 bronchopneumonia for achieving a good outcome, reliable and rapidly available tests for 209 diagnosis of infection are desirable. Culture and PCR testing are undoubtedly the gold standard 210 in the diagnosis of R. equi infection nowadays but, unfortunately, both diagnosis methods take 211 time and have not been considered as prognosis factors for survival. Green aqueous flare was seen 212 in 5/9 SUA foals. The interpretation of this sign is confusing because none of the foals at the 213 moment of the ophthalmologic examination was under any medication than could explain the 214 green coloration in the anterior chamber, nor this ocular finding has been described previously in 215 the literature. Although, in the present study no cytology of the aqueous humor or histopathology 216 was performed that could elucidate the pathogenic mechanism, an acute ocular inflammation with 217 high concentration of PMNN is strongly suggested. Thus, until proven otherwise, green aqueous 218 flare could be considered as an indicative sign for R. equi infection in foals aged 3 weeks to 6 219 months with clinical signs of bronchopneumonia. Further evaluation is warranted to determine 220 whether other infectious diseases that cause uveitis can also cause green flare. 221 Unfortunately, the pathogenesis for uveitis associated with R. equi infection is unknown, but 222 might include dissemination of bacteria to the eye or immune-mediated mechanisms. Immune- 223 complex deposition is also thought to contribute to other EPDs such as polysinovitis.9,12,14,16 224 Further studies are needed to establish the pathogenic mechanism of the ocular presentation of the 11 225 disease. 226 Intraocular signs have been previously associated with poor prognosis in septic foals, in which 227 not only the presence of uveitis was considered a negative survival factor, but also de degree of 228 intraocular inflammation (the most severe the inflammation was, the poorest prognosis).3 229 Similarly, extrapulmonary manifestations of R. equi have been previously associated with poor 230 prognosis, and more specifically, anterior uveitis has been strongly associated with failure to 231 survive.9 The present study not only agrees with Reuss et al. paper, but also suggests that the 232 survival prognosis in R. equi affected foals varies depending on the severity of intraocular 233 inflammation, being foals with mild uveitis more likely to survive. Due to the reduce number of 234 affected foals, there is not enough sample size to establish a statistical relationship between green 235 aqueous flare and prognosis, but since most of the foals with severe uveitis had green aqueous 236 flare, it can be clinically extrapolated that this ocular finding might be associated with a poor 237 prognosis. The reason for this association has not been elucidated yet. So, the question remains 238 whether uveitis was merely an indicator of other EPDs or whether the association with non- 239 survival was real and uveitis represents a more severe systemic response. The present findings do 240 not support the use of degree of uveitis as the only prognosis factor for survival, but might suggest 241 a poor prognosis of survival for more severely affected foals. 242 In the present study active chorioretinal inflammation was seen only in one foal (1/39;2.6%), 243 being bilaterally located around the optic nerve head, coinciding with the most permeable point 244 of the blood-retinal barrier (BRB). This low incidence could be explained by the weakness of the 245 BAB to endogenous damage when compared with BRB,23 by a preference of R. equi for the BAB, 246 or by an underestimation of the chorioretinal lesions due to the severe inflammation of the anterior 247 segment in SUA foals (9/39), preventing adequate funduscopic examination. 12 248 Like many retrospective studies, the herein shows some limitations that should be enlightened. 249 Firstly, the diagnosis of R. equi was performed based on clinical findings, bloodwork, 250 ultrasonography and radiology in all foals, but microbiologic culture or cytology of TBA fluid 251 was performed only in 15.4% of the cases. These two latter diagnostic techniques, together with 252 the polymerase chain reaction (PCR) testing of TBA fluid to identify the virulent vapA gene of R. 253 equi, are considered nowadays as the gold standard for the diagnosis of the disease.11,24 In daily 254 practice, these advanced diagnosis methods are only recommended when the clinical history and 255 clinical findings do not fully match. Thus, in general these techniques are recommended for cases 256 in which clinical doubts are important and justify the risks of a TBA in a very sick foal. In the 257 present study, the majority of sick foals were from endemic farms with recurrent confirmed cases, 258 and the risk of performing a TBA in foals with grave respiratory distress (dyspnea) were not 259 considered by boarded equine internists. Secondly, the relative low number of cases as well as the 260 fact that only the most severely affected foals are referred to a referral center, should be also taken 261 into consideration. 262 In conclusion, this is the first study describing in detail the ophthalmologic findings seen in foals 263 with Rhodococcus equi bronchopneumonia. The severity of anterior uveitis may be considered a 264 survival prognostic factor and until proven otherwise, green aqueous flare could be considered as 265 a suggestive sign of the disease. Findings of this study remark the clinical relevance of performing 266 a complete ocular examination in sick foals, in order to help in the diagnosis and prognosis of 267 uveal diseases, as well as to guarantee visual soundness. 268 REFERENCES 269 1. Davis JL. Ocular manifestations of systemic diseases. In: Equine Ophthalmology 3nd 13 270 edition (ed. Gilger BC). Elsevier Saunders: Missouri 2017:591-623. 271 2. Hughes KJ. 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Blackwell Publishing; Ames, IA 2007:149-182. 324 24. Sellon DC, Besser TE, Vivrette SL, McConnico RS. Comparison of nucleic acid 325 amplification, serology, and microbiologic culture for diagnosis of Rhodococcus equi 326 pneumonia in foals. Journal of Clinical Microbiology 2001;39:1289-93. 327 16 328 329 330 FIGURE LEGENDS 331 Figure 1. Severe anterior exudative uveitis in a 3 months-old foal. Fibrin deposits (white arrows) 332 and diffuse green aqueous flare are observed. 333 334 Foal´s classification Poor outcome (n=9) (n=39) Non-uveitis-affected foals 5/27 non-uveitis affected foals (27 foals; 69.2%) (18.5%) Mildly uveitis-affected foals (MUA) 0/3 MUA foals (3 foals; 7.7%) (0%) Green aqueous flare Green aqueous flare (5 foals; 12.8%) 1/5 Severely uveitis- 4/12 SUA (20%) foals affected foals (SUA) (33.3%) No green aqueous No green aqueous flare flare 3/4 17 (9 foals; 23.1%) (4 foals; 10.2%) (75%) 335 336 Table 1. Ocular findings and outcomes in foals with Rhodococcus equi bronchopneumonia.