The outcomes of SGPV infection in salmon may range from an apparently healthy state to fish with severe respiratory distress, leading to acute mortalities with losses of up to 70% of the animals in the affected tank [6]. Acute disease cases are the easiest to identify and have only been reported from hatcheries, in addition to some cases seen directly after sea transfer [8]. Outbreaks typically start within a couple of weeks following stressful events, such as handling of the fish or production related activities causing noise or vibration [9]. Further, clinical onset is often strikingly synchronised and characterised by morbidity and respiratory distress which rapidly escalates. Mortality often lasts for about four to seven days in an affected tank before spread to neighbouring tanks [7]. The pattern of spread may, however, vary [9]. Moribund fish will commonly display increased opercular movement reflecting respiratory distress, and some animals may display severe muscular rigidity while still alive, sometimes referred to as “live rigor” [9]. Sub-clinical SGPV infections are, however, also common, and such cases are associated with low viral loads in the gills. There is now a strong body of evidence indicating that the SGPV load, clinical manifestation, and pathological changes in gills are closely linked [6,7,8,10,11]. The association of a high virus load and severity of the disease has also been reported in koi carp (Cyprinus carpio) infected with another poxvirus, carp edema virus (CEV), leading to koi sleepy disease (KSD) [12]. The SGPV infection may also be identified in salmon after their transfer to the sea, often in combination with other gill pathogens, commonly diagnosed as complex gill disease (CGD) [13,14]. All components of the epidemiological triad (i.e., the host, the agent, and their shared environment) will undoubtedly affect the outcome of an SGPV infection. While not yet fully understood, stress seems—from both farm observations and experimental trials utilising cortisol implants—to be an important contributing factor [11]. While significant knowledge gaps remain in terms of eliminating salmon gill poxvirus disease (SGPVD), the effects of the disease may reportedly be reduced by stopping feeding, increasing oxygen levels, and avoiding stressful practices [9,15]. 2.1. Is SGPVD a Manifestation of a Dysregulated Host Response in Combination with Respiratory Collapse?External inspection of salmon suffering from SGPVD is often without specific findings, although redness of the abdominal wall and fin-bases may be observed (Figure 2) and has been suggested as an early indication of SGPVD development [9]. Autopsy is also commonly without specific findings apart from occasional reports of moderately pale gills, swollen spleen, and an empty gut [6].In salmon suffering from SGPVD, characteristic histopathological changes are always seen in the gills, and in some cases also in the spleen and kidney, in the form of accumulation of apparently intracellular, amorphous eosinophilic material, interpreted as erythrophagocytosis (i.e., phagocytic destruction of red blood cells). In clinical outbreaks, a large part of the gill respiratory surface is impacted [6]. Apoptosis of gill epithelial cells, confirmed by TUNEL-positive staining, is a hallmark of SGPVD. Apoptotic cells containing SGPV particles may also be observed using TEM (Figure 3). The degree of apoptosis is quantitatively linked to the viral load and disease severity [6,7,8,10,11]. As the apoptotic epithelial cells detach, a widespread adherence of the thin gill lamellae can be seen (Figure 4). In the sub-acute phase of the disease (usually fish having survived a SGPVD outbreak), the inter-lamellar space may become blocked by hyperplastic and hypertrophic gill epithelial cells (Figure 4). Infiltration of leucocytes is not a common feature in SGPVD outbreaks (i.e., in cases where SGPV is suspected to be the only agent causing gill disease), and neither are visible inclusion bodies in the infected cells as described in orthopoxvirus infections [16,17]. Apoptosis is a regulated form of cell death functioning to eliminate unwanted or damaged cells while causing minimal destruction of the surrounding tissues. The specificity of apoptosis is also well suited for the removal of cells identified by the host as virus-infected, and interactions between viral proteins and host apoptotic pathways largely determine the outcome of infections [18]. Virus-driven prevention or reduction of apoptotic responses are reported for several large DNA viruses, including poxviruses [19]. For SGPV, however, the shedding of apoptotic gill epithelial cells leads to the release of infective virus particles into the water, allowing the virus to find new hosts. Another exception to the general anti-apoptotic nature of most poxvirus infections is reported for parapoxvirus, where apoptosis of the infected monocytes leads to impaired antigen presentation [20]. In KSD, impaired respiratory and excretory function of the gills, combined with osmotic, ionic, and acid-base disruption, are suggested as important contributors to clinical manifestation [12].Extensive SGPV-associated erythrophagocytosis has only been described in cases of severe SGPVD with high virus loads [7]. Preliminary investigations give no proof of viremia during the course of the disease [11]. Erythrophagocytosis is reported in koi (Cyprinus carpio) with KSD [21] and in salmon infected with infectious salmon anaemia virus [22]. In the latter case, this is observed to a lesser extent than during SGPVD and with a distribution less restricted to haematopoietic organs. The pathogenesis leading to erythrophagocytosis in SGPVD is not well understood. In mammals, erythrophagocytosis caused by the large DNA virus, Epstein–Barr virus, was shown to be a result of viral interference with a number of immune response mechanisms [23]. Interestingly, dysregulation of the immune responses related to the Epstein–Barr virus reaches a tipping point on the proliferation of the virus to a remarkably high titre [24], and it is tempting to speculate whether a similar scenario contributes to severe outbreaks of SGPVD.