Pigs are usually infected with CSF virus via the oro-nasal route under natural conditions, although infection via the conjunctiva, genital mucosa and abraded skin may occur, as well as transplacental infection of foetuses in utero.

The primary site of replication is the oro-pharyngeal tonsillar tissue. Virus may be present in a variety of cell types, including tonsillar epithelium, but studies have demonstrated that the target cells for the virus are monocyte-macrophages, and that the pathogenesis of the disease as far as it is known results mainly from the release of cytokines by these cells as a result of viral replication within them. Cytokines that have been identified as particularly important include tumour necrosis factor α (TNF-α), interleukin 1α (IL-1α) and interleukin 6 (IL-6). In spite of the fact that the viruses that cause ASF and CSF are very different, the pathogenesis of the two diseases appears to be almost identical, which explains the similarity in presentation of the two diseases in pigs.

After primary replication in the tonsils, the virus is disseminated to other lymphoid tissues via lymphatics, where further replication takes place. A viraemic phase with haematogenous spread to parenchymatous organs follows. Although virus titres are generally lower in parenchymatous organs than in lymphoid tissues, macrophages in the liver (Kupffer cells and intravascular macrophages) and in the lung have demonstrated to play an important role in the pathogenesis of CSF.

CSF is characterised by lymphopenia and thrombocytopenia, which were initially ascribed to direct effects of the virus on lymphocytes and thrombocytes, but have been demonstrated to be due to apoptosis of lymphocytes and aggregation of thrombocytes as a result of cytokines released by infected macrophages. Particularly in the acute form of CSF, haemorrhages are a prominent feature of the infection. These were thought to be due to direct damage to endothelial cells as a result of virus replication, but in fact the damage to endothelium has been found to be minimal, and the haemorrhages are most likely to be due to increased vascular permeability as a result of the effect of inflammatory mediators and impaired clotting ability owing to consumption coagulopathy. Death from acute CSF is most likely due to the severe circulatory disturbances that result in widespread haemorrhages.

The pathogenesis of chronic CSF, resulting from infection with moderately virulent viruses, is similar to that of acute ASF but viraemia is generally low. The course of disease is characterised by a phase during which virus may be detected in serum followed by one when circulating virus is not detectable, after which another viraemic phase occurs. This is attributed to possible immune exhaustion, although antibodies are present. The simultaneous presence of antibodies and circulating virus can result in the deposition of immune complexes in the kidneys, causing glomerulonephritis. During the second phase of viraemia the pigs may suffer secondary bacterial infections.

Infection of pregnant sows in the first trimester with CSF viruses of low virulence can result in persistently infected foetuses. These foetuses develop into piglets that have a persistent viraemia and do not develop antibodies to the virus as they are immunotolerant. The factors that trigger acute fatal CSF in these pigs are unknown.