In 1999, there were reports of a new type of lesion in the hides of captive reared alligators from Florida. Similar lesions were first reported from alligator hides in Louisiana in 2001; however, it wasn't until 2002 that small epizootics became apparent. In 2002, the Louisiana Department of Wildlife and Fisheries began a collaborative effort with the Louisiana State University School of Veterinary Medicine (LSU SVM) to help elucidate the etiology of "PIX" disease, later renamed Lymphohistiocytic Proliferative Syndrome of Alligators (LPSA).

Preliminary work concluded that LPSA was a systemic disease affecting multiple tissues. Based on the results of this preliminary study, particularly the histopathologic evaluation of LPSA tissues, a viral etiology was established as the top differential for LPSA. Further work revealed that LPSA positive alligators were 476 (95% CI: 79.6, 2845.2) times more likely to be seropositive for WNV than LPSA negative alligators. At that point it was also becoming clear that the occurrence of LPSA matched the occurrence of WNV in alligator farms. Another project was performed to further elucidate the association between WNV and LPSA based on results of WNV serology, WNV RT-PCR, and histopathologic evaluation of animals with (treatment) and without (control) LPSA lesions. Results from this study revealed that in the treatment group, 97.5% (95%CI: 92.7-102.3%) of the LPSA skin lesions (TxA) were positive for WNV via RT-PCR. Of the skins within the treatment group that had no LPSA lesions (TxB), 8% (95%CI: 0-16.9%) were positive for WNV. In the control group, all of the skin samples (CxS) were negative for WNV. All alligators in TxA were significantly (p=0.07^-20) more likely to have RT-PCR WNV positive skin than those in CxS, and TxB (p=0.08^-16). There was no significant difference in the recovery of WNV from the skins of alligators from TxB and CxS (p=0.24).

The results of this work support the theory that LPSA is a cutaneous manifestation of chronic WNV exposure/infection in captive reared alligators. Therefore the epidemiology of LPSA follows the epidemiology of WNV and prevention, surveillance and control methods used for WNV should effectively decrease the occurrence of LPSA.