Equine Multinodular Pulmonary Fibrosis: A Newly Recognized Herpesvirus-Associated Fibrotic Lung Disease

Abstract

Pulmonary fibrosis and interstitial lung disease are poorly understood in horses; the causes of such conditions are rarely identified. Equine herpesvirus 5 (EHV-5) is a gamma-herpesvirus of horses that has not been associated with disease in horses. Pathologic and virologic findings from 24 horses with progressive nodular fibrotic lung disease associated with EHV-5 infection are described and compared with 23 age-matched control animals. Gross lesions consisted of multiple nodules of fibrosis throughout the lungs. Histologically, there was marked interstitial fibrosis, often with preservation of an "alveolar-like" architecture, lined by cuboidal epithelial cells. The airways contained primarily neutrophils and macrophages. Rare macrophages contained large eosinophilic intranuclear viral inclusion bodies; similar inclusion bodies were also found cytologically. The inclusions were identified as herpesviral-like particles by transmission electron microscopy in a single horse. In situ hybridization was used to detect EHV-5 nucleic acids within occasional macrophage nuclei. With polymerase chain reaction (PCR), the herpesviral DNA polymerase gene was detected in 19/24 (79.2%) of affected horses and 2/23 (8.7%) of the control horses. Virus genera-specific PCR was used to detect EHV-5 in all of the affected horses and none of the control horses. EHV-2 was detected in 8/24 (33.3%) of affected horses and 1/9 (11.1%) of the control horses. This disease has not been reported before, and the authors propose that based upon the characteristic gross and histologic findings, the disease be known as equine multinodular pulmonary fibrosis. Further, we propose that this newly described disease develops in association with infection by the equine gamma-herpesvirus, EHV-5.

Modulation of lung inflammation by the Epstein-Barr virus protein Zta

“…However, polyomaviruses, which also can be activated by immunosuppression, are not detected in IPF patients (70). An association of interstitial lung disease with herpesvirus infections in horses (83,86) and a cat (45) lends credibility to similar associations in humans.…”

“…The connection between active and/or latent herpesvirus infections has been demonstrated through serological analysis of patients with IPF (81) and by the detection of viral DNA in lung epithelial cells of IPF patients (19,20,75,78). Animal models support the paradigm connecting herpesvirus infections with specific T-helper 2 (Th2) cytokine profiles and alternative macrophage activation (13,60,83) as cofactors for the development of pulmonary fibrosis (80). Moreover, recent evidence indicates that herpesvirus promotes epithelial-mesenchymal transition, a process that occurs during fibrosis (49,69).…”

Quantification ofEquid herpesvirus 5DNA in clinical and necropsy specimens collected from a horse with equine multinodular pulmonary fibrosis

“…The RK13 cells are considered to be permissive to EHV-5 infection but an adjuvant factor may be necessary to cultivate EHV-5 on these cells. EHV-5 isolation is reported rarely: in 2 out of 7 documented cases of EMPF in one report 15 and in zero cases of horses with EMPF in other studies. 6,10,14 In conclusion, the current report presents quantitative analysis of EHV-5 loads in several tissues of an EMPFaffected horse.…”

“…This association was previously reported in 10 out of 33 other cases. 6,10,15 The presence of Candida spp., suspected by cytological exam of BAL #1 and isolated from lung tissue after enrichment, was not confirmed by histology. This could be an overgrowth due to an impairment in the respiratory system.…”

Inflammatory Airway Disease of Horses—Revised Consensus Statement

“…Equid γ‐herpesvirus EHV‐2 and EHV‐5 are commonly identified in respiratory secretions of horses with respiratory disease61, 96 and there is limited evidence that infection with EHV‐2 is more commonly detected in horses with poor performance and airway inflammation 61. Chronic viral infection with EHV‐5 can lead to equine multinodular pulmonary fibrosis (EMPF), which is typically diagnosed in more advanced stages, when horses display clinical signs such as increased respiratory effort and rate as well as hypoxia at rest, pyrexia, weight loss, and poor appetite 97, 98. The presence of specific viruses in the airways may be documented by DNA/RNA or antigen detection (PCR, immunofluorescence), virus isolation early in disease, or a rise in serum antibody titer over the course of disease.…”