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We present the case of an 80-year-old man with type 2 diabetes mellitus receiving corticosteroid therapy for cryptogenic organizing pneumonia who developed cryptococcal cellulitis with a markedly elevated serum cryptococcal antigen (CrAg) titer but no discernible central nervous system (CNS) involvement. As high serum CrAg titers are strongly associated with CNS disease, we compared the patient isolate (designated MA-1) with the Cryptococcus neoformans reference strain KN99, using in vitro growth curves, a murine pulmonary infection model, and whole-genome sequencing. MA-1 grew more slowly than KN99 in tissue culture medium. Mice infected with MA-1 survived longer than those challenged with KN99, although brain dissemination of MA-1 still occurred by day 14, indicating that the strain was neurotropic. Genomic analysis revealed overall similarity to the C neoformans H99 strain but with distinctive structural features, including duplication of chromosome 12, a large deletion on chromosome 5, and multiple single-nucleotide polymorphisms. These alterations may have contributed to altered dissemination dynamics. This case underscores the importance of considering cryptococcosis in refractory cellulitis in immunocompromised patients. High CrAg titers, even without CNS findings, should prompt lumbar puncture and consideration of induction therapy per current guidelines. This integrated clinical and laboratory investigation suggests that pathogen-specific factors, as shown in vitro and in a murine model, may influence the tempo of dissemination in human disease.<\/jats:p>","DOI":"10.1093\/ofid\/ofag334","type":"journal-article","created":{"date-parts":[[2026,5,31]],"date-time":"2026-05-31T11:36:06Z","timestamp":1780227366000},"source":"Crossref","is-referenced-by-count":0,"title":["Primary Cryptococcal Cellulitis With High Antigenemia in an Immunocompromised Host: A Case Report and Laboratory Investigation of the Causative\n                    <i>Cryptococcus neoformans<\/i>\n                    Strain"],"prefix":"10.1093","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0677-1415","authenticated-orcid":false,"given":"Hannah M","family":"Hamad","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School , Worcester, Massachusetts 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