Fatal case of protothecosis in a hematopoietic stem cell transplant recipient after infliximab treatment for graft-versus-host disease

Two studies recently published in Blood have demonstrated that administration of the anti-tumor necrosis factor antibody infliximab to patients with severe graft-versus-host disease (GVHD) is associated with a high risk of subsequent invasive fungal infections.^1,2  We would like to describe an unusual case of disseminated algae infection occurring in a stem cell transplant (SCT) recipient following treatment with infliximab.

A 56-year-old man 562 days after a matched unrelated donor stem cell transplantation was hospitalized for fatigue, rash, and jaundice. He previously had been diagnosed with extensive GVHD of the skin and liver and was receiving prednisone, cyclosporine A, and mycophenolate mofetil. Upon examination, the patient was jaundiced and had multiple pinkish papules on his extremities. Laboratory evaluation showed elevated liver transaminases, significant hyperbilirubinemia, and hyperglycemia. A biopsy of the skin lesions and liver was consistent with GVHD. The patient was treated with a methylprednisolone dose of 2 mg/kg per day, infliximab, and extracorporeal photopheresis. Then, 2 weeks later, he became lethargic and developed bilateral olecranon bursitis and bullous skin lesions. Blood cultures grew Klebsiella pneumoniae and Prototheca wickerhamii. The patient was treated with liposomal amphotericin B (AMB), cefepime, and vancomycin. Culture from a bullous skin lesion also grew P wickerhamii. Blood cultures remained positive for P wickerhamii after 4 days of treatment with AMB despite removal of the central venous catheter. The patient subsequently developed multiorgan failure and died after 5 weeks of hospitalization.

Prototheca is an achlorophyllic algae that is ubiquitous in nature.³  More than 100 human infections have been reported, most commonly involving skin and soft tissues followed by olecranon bursitis, peritonitis, cholangitis, meningitis, and bloodstream infections.^4-8  The great majority of cases have been associated with an underlying immune deficiency.^5,8-11  Treatment of protothecosis involves medical and surgical approaches.³  Results of sensitivity testing indicate Prototheca is susceptible to AMB.^3,5  The utility of the azoles is questionable as most treatment failures have been associated with their use.^3,5 

This is the first case of disseminated protothecosis at our institution and the first report of a very aggressive course of human protothecosis. The infection developed 2 weeks after starting infliximab treatment for GVHD. Infliximab has been associated with reactivation of latent tuberculosis in patients treated for rheumatoid arthritis and Crohn disease. Moreover, increased rates of non-Candida invasive fungal infections in hematopoietic SCT (HSCT) recipients treated with infliximab for GVHD were recently reported.^1,5  The source of the infection in our patient was unclear. Most protothecal infections are attributed to local inoculation at sites of skin defects or trauma.^6,10  The patient had a polymicrobial infection with K pneumoniae and P wickerhamii. It seems likely that the patient was colonized with P wickerhamii on the skin or in the colon, and that infliximab facilitated infection dissemination. Our patient had persistent algaemia despite 4 days of treatment with AMB. He eventually died from multiorgan failure. No previous cases of failure with AMB are reported. The cause of treatment failure was most likely due to a combination of profound immunosuppression and widespread infection.

In conclusion, human protothecosis is a rare disease, but can cause aggressive and fatal infections especially in severely immunosuppressed patients. The use of infliximab to treat steroid-refractory GVHD likely played a role in this case, and it may be wise to use it with great caution in these patients.