A multidisciplinary approach to mucormycosis

Mucormycosis is a life-threatening fungal infection that typically affects highly immunocompromised hosts. In contrast to invasive candidiasis and aspergillosis, the therapeutic arsenal available to treat mucormycosis is limited. In the absence of high-quality comparative studies, the current standard of care involves antifungal therapy with intravenous (IV) liposomal amphotericin B (LAmB), surgical debridement, and, when possible, reduction of immunosuppression. Despite these interventions, mortality in both children and adults is 30–50%.1Otto W.R. Pahud B.A. Yin D.E. Pediatric mucormycosis: a 10-year systematic review of reported cases and review of the literature.J Pediatr Infect Dis Soc. 2019; 8: 342-350Crossref PubMed Scopus (23) Google Scholar, 2Roden M.M. Zaoutis T.E. Buchanan W.L. Knudsen T.A. Sarkisova T.A. Schaufele R.L. et al.Epidemiology and outcome of zygomycosis: a review of 929 reported cases.Clin Infect Dis. 2005; 41: 634-653Crossref PubMed Scopus (2220) Google Scholar Most patients with mucormycosis who survive initial IV therapy are subsequently treated with a prolonged course of oral posaconazole or isavuconazole.1Otto W.R. Pahud B.A. Yin D.E. Pediatric mucormycosis: a 10-year systematic review of reported cases and review of the literature.J Pediatr Infect Dis Soc. 2019; 8: 342-350Crossref PubMed Scopus (23) Google Scholar Here, we report a case of rhino-orbital mucormycosis that highlights several key challenges in the therapeutic management of this infection. An 8-year-old girl with severe aplastic anemia (SAA) refractory to antithymocyte globulin (ATG) and cyclosporine was referred for consideration of hematopoietic stem cell transplantation (HSCT). At that time, an absolute neutrophil count (ANC) of 350 cells/μL prompted initiation of antifungal prophylaxis with voriconazole. No human leukocyte antigen-matched related or unrelated donors were identified. Four months after presentation, a decision was made to perform umbilical cord blood transplantation combined with infusion of CD34+ stem cells obtained from a haploidentical relative. Twelve days prior to HSCT, voriconazole was discontinued and micafungin was initiated to avoid drug-drug interactions between voriconazole and the preparative regimen used for HSCT. During the week prior to HSCT, the patient received cyclophosphamide, fludarabine, equine ATG, total body irradiation, methylprednisolone, mycophenolate mofetil, and tacrolimus. Two days prior to HSCT, the ANC fell to 0 cells/μL. On the day of HSCT (day 0), the patient reported left-sided infraorbital pain. Physical examination, nasal endoscopy, and computerized tomography (CT) of the orbit and sinuses were unrevealing. On day 2, erythema, edema, and non-purulent drainage from the left nasolacrimal duct were noted. A clinical diagnosis of dacrocystitis was initially made, and vancomycin and cefepime were started. On day 4, magnetic resonance imaging (MRI) of the orbit and sinuses demonstrated orbital cellulitis as well as left ethmoid and left maxillary sinusitis. IV LAmB (10 mg/kg) and posaconazole were initiated, and the patient underwent biopsy and debridement of the left maxillary sinus in the operating room. Histopathologic examination of necrotic tissue demonstrated angioinvasion by non-septate hyphae concerning for mucormycosis (Fig. 1A). Bacterial and fungal cultures were negative, but Internal Transcribed Spacer PCR (ITS-PCR) was positive for Lichtheimia corymbifera. Given the anticipated prolonged course of profound neutropenia, a decision was made to initiate granulocyte transfusions (GTXs). On day 5, the patient's mother received G-CSF to mobilize neutrophils for collection. The following day, the patient underwent GTX. Within 24 h of GTX, ANC rose to 16,000 cells/μL (Fig. 1B) which was temporally associated with increased orbital pain and more extensive fat stranding on CT (Fig. 1C). An ethmoid sinus biopsy on day 7 demonstrated a neutrophil-rich inflammatory infiltrate (Fig. 1D). Over the subsequent weeks, the patient underwent multiple debridements and GTXs (Fig. 1B). Four weeks after HSCT, the patient began to improve clinically, and imaging demonstrated stable disease (Fig. 1C). LAmB was continued until day 58 and the patient was ultimately discharged on oral posaconazole for secondary prophylaxis. Three years after transplantation, the patient was well with no evidence of relapsed SAA or mucormycosis, and a decision was made to discontinue posaconazole. Currently, the patient remains well without any signs of mucormycosis 4 years after stopping posaconazole. This case highlights several principles in the management of mucormycosis and demonstrates the therapeutic challenges faced by clinicians. Key determinants of patient outcomes include early administration of appropriate antifungal therapy, emergent surgical debridement, and reversal of immunosuppression.2Roden M.M. Zaoutis T.E. Buchanan W.L. Knudsen T.A. Sarkisova T.A. Schaufele R.L. et al.Epidemiology and outcome of zygomycosis: a review of 929 reported cases.Clin Infect Dis. 2005; 41: 634-653Crossref PubMed Scopus (2220) Google Scholar, 3Cornely O.A. Alastruey-Izquierdo A. Arenz D. Chen S.C.A. Dannaoui E. Hochhegger B. et al.Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium.Lancet Infect Dis. 2019; 19: e405-e421Abstract Full Text Full Text PDF PubMed Scopus (1018) Google Scholar The infectious disease physician plays a crucial role in cases of mucormycosis, coordinating multidisciplinary care across a wide range of medical and surgical subspecialties. Despite the considerable risks of bleeding and peri-operative infection in immunocompromised patients, the benefits of early surgical debridement outweigh these concerns.2Roden M.M. Zaoutis T.E. Buchanan W.L. Knudsen T.A. Sarkisova T.A. Schaufele R.L. et al.Epidemiology and outcome of zygomycosis: a review of 929 reported cases.Clin Infect Dis. 2005; 41: 634-653Crossref PubMed Scopus (2220) Google Scholar, 3Cornely O.A. Alastruey-Izquierdo A. Arenz D. Chen S.C.A. Dannaoui E. Hochhegger B. et al.Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium.Lancet Infect Dis. 2019; 19: e405-e421Abstract Full Text Full Text PDF PubMed Scopus (1018) Google Scholar The role of adjunctive therapies in the management of mucormycosis is controversial.3Cornely O.A. Alastruey-Izquierdo A. Arenz D. Chen S.C.A. Dannaoui E. Hochhegger B. et al.Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium.Lancet Infect Dis. 2019; 19: e405-e421Abstract Full Text Full Text PDF PubMed Scopus (1018) Google Scholar While high-quality evidence is lacking, GTX and hyperbaric oxygen are occasionally used in clinical practice.2Roden M.M. Zaoutis T.E. Buchanan W.L. Knudsen T.A. Sarkisova T.A. Schaufele R.L. et al.Epidemiology and outcome of zygomycosis: a review of 929 reported cases.Clin Infect Dis. 2005; 41: 634-653Crossref PubMed Scopus (2220) Google Scholar, 3Cornely O.A. Alastruey-Izquierdo A. Arenz D. Chen S.C.A. Dannaoui E. Hochhegger B. et al.Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium.Lancet Infect Dis. 2019; 19: e405-e421Abstract Full Text Full Text PDF PubMed Scopus (1018) Google Scholar, 4West K.A. Gea-Banacloche J. Stroncek D. Kadri S.S. Granulocyte transfusions in the management of invasive fungal infections.Br J Haematol. 2017; 177: 357-374Crossref PubMed Scopus (43) Google Scholar A major limitation of the literature is that these interventions have primarily been initiated at late stages of infection in extremely ill patients. Our robust experience with GTX allowed for the rapid implementation of GTX, which maintained the ANC above 500 cells/μL during her course (Fig. 1B). An important yet unanswered question about the mechanism of action of GTX relates to the ability of transfused neutrophils to migrate to the site of infection. Biopsy specimens obtained after GTX demonstrated abundant neutrophilic infiltration (Fig. 1D). The presence of neutrophils in the infected tissue at a time when the patient lacked any detectable endogenous neutrophil production strongly suggests that transfused donor neutrophils are capable of homing to the site of infection. Future efforts to quantify the efficiency of this process and determine the fungal killing capacity of transfused neutrophils would have important implications for the rational dosing of GTX. Following aggressive surgical debridement and LAmB, most patients with mucormycosis receive secondary azole prophylaxis. No data are available to guide clinicians on the decision of whether patients can safely discontinue azole prophylaxis. Our patient's sustained immune reconstitution combined with her young age and well-established toxicities of long-term posaconazole5Benitez L.L. Carver P.L. Adverse effects associated with long-term administration of azole antifungal agents.Drugs. 2019; 79: 833-853Crossref PubMed Scopus (118) Google Scholar provided the rationale for stopping prophylaxis 3 years after HSCT. Optimal management of mucormycosis depends on the rapid assembly of a multidisciplinary team to initiate surgical, antimicrobial, and immune-based therapies early during infection. Comparative trials of currently available therapies as well as the development of novel therapeutic strategies are desperately needed to improve patient outcomes for this highly lethal infection. This work was supported by the Division of Intramural Research of the NIAID, NHLBI, NCI, NEI, and NIH Clinical Center, NIH.