Nivolumab plus interferon-γ in the treatment of intractable mucormycosis

Acquired immunosuppression is an important complication of major trauma and might contribute to the development of severe fungal infections in these patients. Here, we describe a patient with extensive abdominal mucormycosis unresponsive to conventional therapy who was treated successfully with immunostimulating drugs. A previously healthy 30-year old woman sustained pelvic and femur fractures, extensive soft-tissue abdominal and pelvic damage, pulmonary contusion, and second-degree burns in the terrorist bombing in Brussels in March, 2016. The patient's early hospital course was complicated by sepsis, femur osteomyelitis, and deep wound infections with multi-drug-resistant Enterobacteriaceae. On day 15 after admission to the intensive care unit, results of CT analysis showed gastric and splenic necrosis (figure); gastric biopsy results available on day 18 revealed invasive mucormycosis, and treatment was started with liposomal amphotericin-B and posaconazole. On day 22, gastrectomy and splenectomy were done; pathology showed invasive mucormycosis in the stomach and spleen with extension into peritoneal and vascular structures, but additional debridement was not feasible. Because of the poor prognosis and immunosuppression, as shown by a low absolute lymphocyte count, low monocyte HLA-DR expression, and increased expression of programmed death-1 (PD-1) on T-cells (appendix), immunoadjuvant therapy with interferon-γ (Immukine, Boehringer, Brussels, Belgium; 100 μg three times weekly for five doses) was started on day 28, followed by a single 250 mg dose of nivolumab (Opdivo, BMS, Braine l'Alleud, Belgium) on day 30. Subsequent immunological examinations showed increases in absolute lymphocyte count, monocyte HLA-DR expression, and CD8 T-cells, and decreased T-cell PD-1 expression (appendix). The patient improved slowly, and repeat CT scans showed no residual infection. The patient was discharged from the intensive care unit 80 days after admission. This patient, with well documented fungal sepsis, showed typical features of post-aggression immunosuppression involving defective innate and adaptive immunity.1Netea MG Joosten LA van der Meer JW Kullberg BJ van de Veerdonk FL Immune defense against Candida fungal infections.Nat Rev Immunol. 2015; 15: 630-642Crossref PubMed Scopus (316) Google Scholar, 2Kullberg BJ van de Veerdonk F Netea MG Immunotherapy: a potential adjunctive treatment for fungal infection.Curr Opin Infect Dis. 2014; 27: 511-516Crossref PubMed Scopus (20) Google Scholar Interferon-γ and the anti-PD-1 monoclonal antibody nivolumab reversed these defects. Interferon-γ restores monocyte function and has been used as rescue therapy for life-threatening fungal infections in patients not responding to conventional treatment.1Netea MG Joosten LA van der Meer JW Kullberg BJ van de Veerdonk FL Immune defense against Candida fungal infections.Nat Rev Immunol. 2015; 15: 630-642Crossref PubMed Scopus (316) Google Scholar, 2Kullberg BJ van de Veerdonk F Netea MG Immunotherapy: a potential adjunctive treatment for fungal infection.Curr Opin Infect Dis. 2014; 27: 511-516Crossref PubMed Scopus (20) Google Scholar, 3Delsing CE Gresnigt MS Leentjens J et al.Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: a case series.BMC Infect Dis. 2014; 14: 166Crossref PubMed Scopus (152) Google Scholar Nivolumab binds to PD-1, blocks interaction with its ligands, PD-L1 and PD-L2, and releases PD-1 pathway-mediated inhibition of T-cell proliferation and cytokine production. Anti-PD-1 has shown activity in animal models of fungal sepsis and in patients with chronic hepatitis C virus infection.4Attanasio J Wherry EJ Costimulatory and coinhibitory receptor pathways in infectious disease.Immunity. 2016; 44: 1052-1068Summary Full Text Full Text PDF PubMed Scopus (159) Google Scholar A phase I clinical trial of nivolumab in the treatment of severe sepsis is about to begin (NCT02960854). Combination immunotherapy has been proposed as a possible advance in sepsis treatment.5Hotchkiss RS Opal S Immunotherapy for sepsis—a new approach against an ancient foe.N Engl J Med. 2010; 363: 87-89Crossref PubMed Scopus (284) Google Scholar To our knowledge, this is the first report showing efficacy of such an approach in a patient with life-threatening fungal infection unresponsive to conventional therapy. RSH has research support funding from Bristol Myers Squibb, the maker of nivolumab, and is also doing clinical trials with anti-PD-L1, an investigational drug made by Bristol Myers Squibb, in sepsis. All other authors declare no competing interests. The patient provided consent for publication of this letter. Download .pdf (.26 MB) Help with pdf files Supplementary appendix