Investigation of the cause of death in a gene-therapy trial.
We present a case of disseminated histoplasmosis, complicated by retroperitoneal bleeding and leading to death, in a patient who was receiving systemic immunosuppressive therapy for rheumatoid arthritis and who was enrolled in a gene-therapy trial. This trial was designed to evaluate intraarticular delivery of a tumor necrosis factor alpha (TNF-alpha) antagonist, through an adeno-associated virus (AAV) type 2 delivery system, for inflammatory arthritis. The patient's receipt of concurrent anti-TNF-alpha therapy and other immunosuppressive therapy while she was living in an area where histoplasmosis was endemic was thought to be the most likely explanation for the infection; the evidence presented suggests that this fatal infection was unlikely to have been related to exposure to the agent administered in the gene-therapy trial. This case reinforces the importance of considering infectious complications, such as those from endemic mycoses, in patients receiving treatment with a TNF-alpha antagonist and the importance of having a well-designed monitoring plan when subjects in a research study become ill. (ClinicalTrials.gov number, NCT00126724.)
Frank
Karen M
KM
Department of Pathology, University of Chicago Medical Center, Chicago, IL 60637, USA. kfrank@uchicago.edu
Hogarth
D Kyle
DK
Miller
Jonathan L
JL
Mandal
Saptarshi
S
Mease
Philip J
PJ
Samulski
R Jude
RJ
Weisgerber
Glen A
GA
Hart
John
J
D000328:Adult; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000628:therapy*; D002423:Cause of Death; D000229:Dependovirus / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors; D006406:Hematoma / Q000000981:diagnostic imaging / Q000209:etiology*; D006658:Histoplasma / Q000302:isolation & purification; D006660:Histoplasmosis / Q000209:etiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008099:Liver / Q000382:microbiology / Q000473:pathology; D009894:Opportunistic Infections / Q000209:etiology*; D011859:Radiography; D012187:Retroperitoneal Space / Q000000981:diagnostic imaging; D013921:Thrombocytopenia / Q000209:etiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics
D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha