Emergence of Cunninghamella As a Pathogenic Invasive Mold Infection in Allogeneic Transplant Recipients

Case Report

Emergence of Cunninghamella As a Pathogenic Invasive Mold Infection in Allogeneic Transplant Recipients Lynne Strasfeld,1 Luis Espinosa-Aguilar,1 James L. Gajewski,2 Peter Stenzel,3 Agustin Pimentel,4 Elana Mater,2 Richard T. Maziarz2 Clinical Practice Points
Cunninghamella, a relatively infrequent cause of


Despite currently available treatment approaches, the

mucormycosis, is associated with aggressive and often fatal disseminated invasive fungal infection in hematopoietic stem cell transplant (HSCT) recipients, in particular those receiving high-dose immune suppression.
Polyene-based antifungal agents, such as amphotericin B and its lipid derivatives, are first-line therapy for invasive mucormycosis.

attributable mortality of mucormycosis remains very high. Our single-center experience suggests that infection with Cunninghamella species portends worse outcomes.
The impact of prophylactic approaches (eg, with extended-spectrum azoles such as posaconazole) in preventing this infection in high-risk patients awaits further investigation.

Clinical Lymphoma, Myeloma & Leukemia, Vol. 13, No. 5, 622-8 ª 2013 Elsevier Inc. All rights reserved. Keywords: Cunninghamella, Mucormycosis, Stem cell transplantation, Zygomycosis

Introduction Hematopoietic stem cell transplant (HSCT) recipients are at increased risk for opportunistic fungal infections, with risk largely related to treatment-associated cytopenia and to immunosuppressive therapies used in the prophylaxis and treatment of acute and chronic graft-versus-host disease (GVHD)1-3 Over the past few decades, the epidemiology of invasive fungal infection (IFI) has changed. Mold infections have become increasingly common, and although Aspergillus remains by far the most prevalent, there has been an observed increase in Zygomycetes infections in HSCT recipients and patients with hematologic malignancies.4-7 From the Zygomycetes class, the members of the order Mucorales cause most human disease,8 with Rhizopus the most common species reported.9 More recently, other species have been documented with increasing frequency.10 In this report, we describe 3 cases of HSCT-related Cunninghamella, an

1

Division of Infectious Diseases, Oregon Health and Science University, Portland, OR 2 Center for Hematologic Malignancies, OHSU Knight Cancer Institute, Portland, OR 3 Department of Pathology, Oregon Health and Science University, Portland, OR 4 Department of Hematology and Medical Oncology, University of Miami, Miami, FL Submitted: Jan 3, 2013; Revised: May 1, 2013; Accepted: May 2, 2013; Epub: Jul 10, 2013 Address for correspondence: Lynne Strasfeld, MD, 3181 SW Sam Jackson Park Road, mail code L-457, Portland, Oregon, 97239 Fax: þ1-503-494-4264; e-mail contact: [email protected]

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unusual but often fatal cause of mucormycosis, and review data from our center that suggests that this IFI may be more frequently recognized in the future.

Patients and Methods Patient Population All recipients of allogeneic HSCTs treated at Oregon Health and Science University (OHSU) with a diagnosis of proven or probable invasive fungal infection with a Zygomycetes during the period from January 1, 2005 through December 31, 2010 were included in the study. All data were collected by review of clinical, laboratory, pathologic, and clinical transplantation databases, as well as electronic and paper medical records, with the use of standardized data collection forms. All patients were observed for a minimum of 60 days or until death. The study was approved by the Institutional Review Board at OHSU.

Antifungal Prophylaxis and Treatment of Proven or Probable Mucormycosis All HSCT recipients received antifungal prophylaxis. Before December 2007, fluconazole was the standard agent for antifungal prophylaxis in transplant recipients at our center. After the US Food and Drug Administration approved posaconazole in 2007 as antifungal prophylaxis for patients with severe steroid-requiring GVHD,11 our institution moved to incorporate extended-spectrum azoles as the standard prophylaxis for such high-risk patients. We

2152-2650/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.05.002

use posaconazole as our first-line antifungal prophylactic agent for patients with severe GVHD. Voriconazole is used for patients with proven or probable invasive aspergillosis as primary treatment12 and/or as secondary prophylaxis13 and for prophylaxis for patients with active GVHD of the gut or another process interfering with transluminal absorption of posaconazole.14 Micafungin is our second-line agent for antifungal prophylaxis in high-risk recipients, typically when azole-based therapy is contraindicated (as with drugdrug interaction or documented adverse event with azoles). Firstline therapy for mucormycosis at our institution is a lipid-based amphotericin B product. Posaconazole is used as second-line therapy for patients who are intolerant or refractory to amphotericin B derivatives,15 in combination with a polyene or as oral continuation therapy after a course of parenteral treatment with a polyene.

Immune Suppression: GVHD Prophylaxis and Treatment GVHD prophylaxis for conventional myeloablative HSCT was administered with a modification of the 3-drug regimen published by Ross et al.16 Specifically, methotrexate (MTX) and cyclosporine (CsA ) were administered as described, but methylprednisolone was initiated at 0.5 mg/kg (decreased from the published dose of 1 mg/ kg) beginning day þ7, with taper schedule to begin at day þ28. Reduced-intensity HSCT procedures used CsA and mycophenolate mofetil (MMF), beginning CsA on day e3 and continuing while maintaining CsA levels targeting 500 ng/ml initially, between 300 and 400 ng/ml after day þ28, and then tapering by 6% per week from day þ84 through day þ180. MMF was administered at 1 g 3 times a day through day þ28, twice daily through day þ56, and then discontinued.17 For patients in whom grade 2 to grade 4 acute GVHD developed, standard treatment of 2 mg/kg of prednisone equivalent was administered and maintained for 7 days before initiation of a taper, with the goal of 0.25 mg/kg by day þ28 of treatment. Taper of calcineurin inhibitor and corticosteroids was performed as clinically permissible. Standard definitions for invasive fungal infection were used as described elsewhere.18

Results A retrospective chart review from cases at our center between January 1, 2005 and December 31, 2010 identified 13 cases of mucormycosis in HSCT recipients (Table 1). All cases occurred in allogeneic transplant recipients; over the same period, a total of 422 allogeneic HSCTs were performed, with a cumulative incidence of mucormycosis of 3.1% in this population. The median time to diagnosis of mucormycosis was 148 days (range, 52-1090 days) after transplantation. Species-level identification was available for 92% (12 of 13) of cases, 10 by culture and 2 by molecular diagnostics. The most common species was Rhizopus (7 of 12), but interestingly 3 of the 13 were Cunninghamella (see Cases 1-3 further on), a sizeable percentage of our overall cases (23%). Over the same period, there were 22 cases of proven or probable invasive aspergillosis in this cohort, for a cumulative incidence of 5.2%.

Case Reports Case 1 A 59-year-old woman with a history of diabetes mellitus and breast cancer was diagnosed with myelodysplastic syndrome (MDS)

(World Health Organization classification: refractory anemia) in July 2004, for which she was treated in a trial with ezatiostat HCl (TLK199) and then with darbepoietin alfa. Despite these interventions, she remained leukopenic with intermittent neutropenia. Bilateral pulmonary nodules were noted in December 2005, and the lung biopsy specimen revealed only nonspecific inflammatory changes on histopathologic examination. Culture results were negative, but with concern for IFI she was treated with empirical voriconazole. She proceeded to myeloablative HSCT from a human leukocyte antigenematched sibling donor in March 2006. The conditioning regimen was targeted busulfan and cyclophosphamide, with GVHD prophylaxis of CsA, prednisone, and shortcourse MTX. Voriconazole was continued as secondary prophylaxis for possible pulmonary aspergillosis, noting pre-transplantation pulmonary nodules from a nondiagnostic biopsy specimen. The post-transplantation course was complicated by cytomegalovirus (CMV) reactivation (day þ43), BK virus cystitis (day þ50), and biopsy-proven chronic extensive GVHD of the gastrointestinal tract (day þ115) requiring treatment with corticosteroids (2 mg/kg/d prednisone equivalent). On day þ147, a new lesion of the left calf was noted and diagnostic skin biopsy was arranged. Eight days later she was hospitalized for progressive dyspnea and pleuritic chest pain. Physical examination was remarkable for hypoxia, new-onset atrial fibrillation, diminished breath sounds throughout the right lung, and a 3-cm black eschar with surrounding erythema of the left calf (Figure 1A). Laboratory studies revealed pancytopenia (absolute neutrophil count, 800 cells/mm3), and computed tomography (CT) of the chest demonstrated a large right-sided pleural effusion with scattered bilateral pulmonary nodules, some with surrounding inflammation with ground-glass appearance (Figure 1B). Pathologic examination of the skin biopsy specimen revealed numerous nonseptate, broad-based hyphal elements with evidence of vasculitis, and the culture ultimately grew Cunninghamella. Voriconazole was changed to posaconazole (200 mg orally 4 times daily dosing schedule), prednisone was tapered, and the left calf wound was debrided. Soon thereafter the patient became lethargic, and magnetic resonance imaging of the brain revealed an acute left posterior parietal infarct. Her mental status declined and she died 15 days after the initial appearance of the calf lesion (day þ162) and 5 days after initiation of posaconazole. Autopsy showed evidence of widespread disseminated angioinvasive mold involving the pericardium, myocardium, lungs, diaphragm, gastrointestinal system, lymph nodes, skin, and brain (Figure 1, C and D).

Case 2 A 39-year-old man was diagnosed with MDS (World Health Organization classification: refractory anemia with excess blasts-2) in December 2007. He underwent a conventional myeloablative HSCT from a matched unrelated donor (MUD) in April 2008 with targeted busulfan and cyclophosphamide conditioning, and GVHD prophylaxis with CsA, prednisone, and short-term MTX. The post-transplantation course was complicated by BK virus cystitis (day þ39) and grade 3 acute GVHD of the skin and gastrointestinal tract (day þ54), which was managed with an increased dose of corticosteroids (2 mg/kg/d of prednisone equivalent) along with a switch of prophylaxis from fluconazole to voriconazole. CMV reactivation

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624

Underlying Diagnosis

Sex, Age (years)

Donor Type

M, 30

AML

MUD

F, 33

T-ALL

MUD

F, 59

MDS

Related (Sib)

F, 59

T-PLL

Sib

M, 39

MDS

MUD

M, 64

Myelofibrosis

MUD

M, 37

T-ALL

MUD

M, 54

MM

MUDg

M, 59

ALL

MUD

M, 39 M, 60 M, 67

AML CLL T-PLL

MUD MUD MUD

M, 69

AML

MUD

Complications Relapsed disease (salvage FLAG IDA), GVHD grade 2 Relapsed (salvage FLAG IDA), CMV GVHD chronic extensive, CMV, BK virus cystitis Relapsed (salvage alemtuzumab), CMV GVHD grade 3, CMV, BK virus cystitis GVHD grade 3, PIV-3, CMV GVHD grade 3, MAHA, BK virus cystitis cGVHD grade 4, CMV, relapsed GVHD grade 3, relapsed, BO Relapsed GVHD grade 2, BO GVHD grade 2, IPS, CMV cGVHD

Time of Diagnosis After Transplantation (year)

Antifungal Prophylaxis

Zygomycetes Species

Site of Infection

Treatment

Outcome of Infection

þ92 (2005)

FLU

Zygomycetes spa

Lung

AmBb/ POSA

Survivedc

þ734 (2006)

FLU

Mucor

Rhinoorbital

AmBb/ surgery

Survivedd

þ147 (2006)

VORIe

Cunninghamella

Dissem

POSA/ surgery

Deceased þ162

þ245 (2006)

FLU

Mucor

Rhinoorbital/cerebral

AmBb/ POSA/ surgery

Deceased þ263

þ173 (2008)

FLU/VORI

Cunninghamella

Dissem

AmBb

Deceased þ184

þ148 (2009)

FLU/VORIe

Rhizopusf

Lung

AmBb/ surgery

Deceased þ200

þ77 (2009)

VORI/MICA

Rhizopus

Lung

AmBb

Deceased þ80

þ52 (2008)

FLU

Rhizopus

Lung

AmBb/ POSA/ surgery

Survivedh

þ1090 (2010)

FLU

Rhizopus

Rhinoorbital

AmBb/ surgery

Survivedi

þ482 (2010) þ114 (2010) þ76 (2010)

VORIe VORIe VORI

Rhizopusf Rhizopus Rhizopus

Lung Lung Lung

AmBb AmBb/ POSA AmBb/ POSA

Deceased þ543 Deceased þ139 Deceased þ131

þ274 (2010)

VORI

Cunninghamella

Lung

AmBb

Deceased þ287

ALL ¼ acute lymphoblastic leukemia; AML ¼ acute myelogenous leukemia; BO ¼ bronchiolitis obliterans; cGVHD ¼ chronic GVHD; CLL ¼ chronic lymphocytic leukemia; CMV ¼ cytomegalovirus; Dissem ¼ disseminated; FLAG IDA ¼ fludarabine, cytarabine, idarubicin and granulocyte colony-stimulating factor; FLU ¼ fluconazole; GVHD ¼ graft-versus-host disease; IPS ¼ idiopathic pneumonia syndrome; MAHA ¼ microangiopathic hemolytic anemia; MDS ¼ myelodysplastic syndrome; MICA ¼ micafungin; MUD ¼ matched unrelated donor; MM ¼ multiple myeloma; PIV ¼ parainfluenza virus; POSA ¼ posaconazole; Sib ¼ sibling; T-ALL ¼ T-cell acute lymphocytic leukemia; T-PLL ¼ T-cell prolymphocytic leukemia; VORI ¼ voriconazole. a Diagnosed on pathologic examination. b Amphotericin B derivative, either Ambisome or Abelcet. c Died of relapsed disease (þ213). d Died of relapsed disease (þ820). e For treatment of previous possible, probable, or proven invasive pulmonary aspergillosis. f Diagnosed with use of molecular diagnosis. g Previous autologous stem cell transplantation in 2005. h Died of staphylococcal bacteremia (> 1 year). i Died of relapsed disease (þ1150).

Emergence of Cunninghamella, an Invasive Mold

Clinical Lymphoma, Myeloma & Leukemia October 2013

Table 1 Cases

Lynne Strasfeld et al Figure 1 (A) Left Calf Eschar With Surrounding Erythema. (B) Chest Computed Tomography With Large Right-Sided Pleural Effusion and Scattered Bilateral Pulmonary Nodules. (C) Aortic Tissue From Autopsy Demonstrating Nonseptate Hyphae. (D) Diaphragm Tissue From Autopsy Demonstrating Broad Nonseptate Hyphae on Gomori Methenamine Silver Stain

occurred on day þ58, with pancytopenia requiring growth factor support. After initial response to corticosteroids, GVHD flared during steroid taper (day þ115), and budesonide was added to prednisone and CsA. CT revealed long-segment distal bowel enteritis but no evidence of pulmonary nodules or consolidations. The patient continued to receive immune suppression and he was subsequently readmitted on day þ173 with progressive abdominal pain, weight loss, and early satiety. Physical examination was notable for abdominal tenderness, a firm subcutaneous erythematous nodule of the left forearm, and a 1-cm shallow ulceration with surrounding necrosis and erythema at the left medial malleolus (Figure 2A). Biopsy of a gastric antral ulcer revealed invasive hyphal elements extending into the superficial lamina propria (Figure 2B) and evidence of active GVHD from duodenal tissue. A CT demonstrated multiple bilateral pulmonary nodules and hypodensities of the thyroid, liver, spleen, and kidneys (Figure 2C). Voriconazole was changed to liposomal amphotericin B (5 mg/kg/d, subsequently increased to 7.5 mg/kg/d) and prednisone was rapidly tapered. The specimen from skin biopsy of the left ankle lesion revealed branching hyphae within vessel walls and lumens (Figure 2D), and cultures grew Cunninghamella (amphotericin minimal inhibitory concentration [MIC], 0.5 mg/mL at 24 and 48 hours; posaconazole MIC, 0.25 mg/mL at 24 hours and 0.5 mg/mL at 48 hours; Fungus Testing Laboratory, University of Texas Health Science Center, San Antonio, TX). His clinical status steadily declined, with suspicion of brain involvement by magnetic resonance imaging, and he died 11 days after admission and 10 days after initiation of liposomal amphotericin B (day þ184). A postmortem examination was not obtained.

Case 3 A 69-year old man with a history of idiopathic thrombocytopenic purpura was diagnosed with acute myelogenous leukemia (AML) in July 2009. He underwent a nonmyeloablative HSCT from a MUD in March 2010, with busulfan 3.2 mg/kg, fludarabine 100 mg/ m2  3 days, total body irradiation conditioning with 200 cGy administered in a single fraction, and GVHD prophylaxis with CsA and MMF. The post-transplantation course was complicated by altered mental status (day þ23), suspected to be a complication of calcineurin inhibitor therapy and/or vascular dementia; CMV reactivation (day þ40); and grade 2 acute GVHD of the gastrointestinal tract (day þ40), which was treated with corticosteroids (2 mg/kg/d of prednisone equivalent, with a rapid taper, and ultimately managed with topical budesonide alone until November 2010), along with a change of antifungal prophylaxis from fluconazole to voriconazole (voriconazole continued until October 2010). He was subsequently admitted in late 2010 (November to December) with biopsy-confirmed GVHD of the skin and colon, so tacrolimus and systemic corticosteroids (1 mg/kg/d of prednisone equivalent, with subsequent taper) were resumed, along with resumption of voriconazole prophylaxis. Prompted by a new dry cough in mid-December 2010, chest CT was performed, revealing new right middle lobe peribronchial ill-defined nodules with a ground-glass appearance. Bronchoscopy with bronchoalveolar lavage (day þ274) demonstrated hyphal elements on cytopathologic examination, and culture was positive for Cunninghamella species. The patient was prescribed amphotericin B 2 days after bronchoscopy. Follow-up chest CT at 2 weeks revealed marked worsening, with extensive bilateral areas of nodular consolidation in a

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Emergence of Cunninghamella, an Invasive Mold Figure 2 (A) Left Medial Malleolus Ulceration With Surrounding Erythema. (B) Gastric Biopsy Demonstrating Nonseptate Hyphae. (C) Chest CT With Right Lung Nodule. (D) Dermal Biopsy Specimen Demonstrating Broad Nonseptate Hyphae

bronchovascular distribution (Figure 3). Given the suspicion for progressive IFI in this patient with steroid-refractory GVHD, the care plan was transitioned to comfort measures and the patient died shortly thereafter on day þ287.

Discussion

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Zygomycetes are ubiquitous molds found in soil and decaying organic matter.19 The major mode of infection in humans is inhalation of spores, but percutaneous and gastrointestinal routes are also described.9 Disease occurs almost exclusively in immunesuppressed individuals;20 the most commonly described underlying risk factors are hematologic malignancies, hematopoietic stem cell and solid organ transplantation, diabetes mellitus, iron overload and chelation therapy, and corticosteroid use.21,22 In a large multicenter prospective surveillance study of HSCT recipients from 2001 to 2006, Zygomycetes represented 8% of all IFIs.23 An increase in cases of mucormycosis in HSCT recipients has been observed over time,1-3 a trend that may be related to a more immune-suppressed patient population in the context of higher risk transplantations, improvement in diagnostic methods with molecular techniques, patient survival with often prolonged courses of voriconazole treatment or prophylaxis, and/or unrecognized Zygomycetes infections that were previously treated with empirical amphotericin products and are now “unmasked” in the setting of voriconazole or echinocandin use.6 Cunninghamella has been noted to be a relatively uncommon cause of mucormycosis.24 Of the 465 culture-identified cases described by Roden et al, only 7% were Cunninghamella.25 There are a handful of anecdotal case reports of Cunninghamella infection in patients receiving hematopoietic stem cell transplantation,26-29 and Cunninghamella

Clinical Lymphoma, Myeloma & Leukemia October 2013

represents a rare subset within larger series of mucormycosis infections in HSCT recipients and patients with malignancy.4,5 A large single-center study at the Fred Hutchinson Cancer Research Center identified underlying MDS and severe GVHD as significant risk factors for infection with Zygomycetes.5 GVHD (acute and chronic) has been associated with non-Aspergillus mold infections,8,30,31 and a majority of the mucormycosis cases reported in HSCT recipients have underlying GVHD.32 The majority of patients presented in this series and all 3 of the patients we describe with Cunninghamella had steroid-dependent GVHD. Almost all presented relatively late in their post-transplantation course (12 of 13 at > 60 days after transplantation and 3 at > 1 year after transplantation), consistent with the published description of mucormycosis as a late infection relative to other IFIs.5,6 The primary site of infection varies as a function of the host population. In the largest series of Zygomycetes infections published to date,25 pulmonary mucormycosis constituted more than half of the cases in patients with malignancy who had received an HSCT. Although disseminated disease can originate from any primary site, lung is the single most common site associated with dissemination.9 Mortality related to Zygomycetes infection in patients with hematologic malignancy and/or HSCT recipients is substantial, with reports ranging from 64% to 91%, and with case fatality highest in the setting of disseminated disease.6,25,33 Disease caused by Cunninghamella tends to follow a fulminant course, with an overall mortality rate approaching 80%9 and with higher mortality when compared with other Zygomycetes species.25 In our case series, mucormycosis-attributable mortality was 69%, and 100% for the 3 cases of Cunninghamella infection (Table 1). There are speculated to be host and microbe factors, which if validated by

Lynne Strasfeld et al Figure 3 CT of the Chest With Extensive Bilateral Consolidation in a Bronchovascular Distribution

recipients with severe GVHD. Although posaconazole has been our preferred prophylactic antifungal agent for this high-risk population since 2007, it was interesting to note that none of the 13 patients in our series (9 in the posaconazole era) were receiving posaconazole prophylaxis at the time of diagnosis of mucormycosis, either out of concern for enteral absorption or because they did not have steroiddependent GVHD.

Conclusion

further study may help explain the more aggressive course observed with this species. Attenuated innate host immune response to Cunninghamella has been recently described in an in vitro model,34 as has increased virulence of Cunninghamella bertholletiae relative to other members of the order Mucorales in an experimental neutropenic rabbit model.35 The diagnosis of mucormycosis can be challenging. In patients with hematologic malignancy, an antemortem diagnosis is made in only 23% to 50% of cases.8 Diagnosis, when established, is often made when the infection is already disseminated, as in 2 of the 3 cases of Cunninghamella infection we describe. Sputum and bronchoalveolar lavage typically have low sensitivity.4 Histologic examination of tissue is the preferred method of diagnosis, but extensive necrosis, hyphal fragmentation, and poor staining of the thin hyphal walls can render microscopic visualization difficult. Polymerase chain reaction assays are a promising alternative for diagnosis of IFIs.36,37 Early diagnosis is essential to successful treatment, and delay in effective antifungal therapy is a predictor of poor outcome.33 Polyene-based antifungal agents, such as amphotericin B and its lipid derivatives, aggressive surgical debridement (for localized disease), and control or reversal of disease or immune suppression are the mainstays of therapy. Treatment of Cunninghamella infection is complicated by higher MICs to polyene-based antifungals, relative to other Zygomycetes.38 A large in vitro study of clinical cultures reported 63% susceptible to amphotericin B and 75% susceptible to posaconazole for 13 Cunninghamella isolates.39 Posaconazole has been used as salvage therapy for mucormycosis40 but lacks a formal indication for this use. Patients with gastrointestinal GVHD are at high risk for malabsorption of oral posaconazole, and therapeutic drug monitoring may be warranted during treatment.41 Data from animal models42 and the report of breakthrough Zygomycetes infections in patients receiving posaconazole prophylaxis43 raise concerns about the efficacy of posaconazole. In the absence of more clinical data, posaconazole cannot be recommended as primary treatment for mucormycosis but can be considered as an alternative for patients who cannot tolerate first-line polyene-based therapy.44 With regard to prevention, there are data11 indicating that posaconazole prophylaxis decreases the risk for IFI in transplant

Non-Aspergillus mold infections in HSCT recipients have increased over the past few decades. Cunninghamella is a less common cause of mucormycosis and is associated with an aggressive course, often with fatal outcome despite antifungal therapy. Future work in this field is needed to improve diagnostic, preventive, and treatment strategies for this infection. Furthermore, the aggressive nature of Cunninghamella infection, with its clinical presentation of widespread hematogenous dissemination, warrants further investigation, in particular the interaction of the organism with the host immune system.

Acknowledgements We are extremely grateful for the skillful technical assistance generously provided by Thomas Thomas.

Disclosure The authors have stated that they have no conflicts of interest.

References 1. Leather HL, Wingard JR. Infections following hematopoietic stem cell transplantation. Infect Dis Clin North Am 2001; 15:483-520. 2. Mackall C, Fry T, Gress R, Peggs K, Storek J, Toubert A. Background to hematopoietic cell transplantation, including post transplant immune recovery. Bone Marrow Transplant 2009; 44:457-62. 3. Ramaprasad C, Pouch S, Pitrak DL. Neutrophil function after bone marrow and hematopoietic stem cell transplant. Leuk Lymphoma 2010; 51:756-67. 4. Kontoyiannis DP, Wessel VC, Bodey GP, Rolston KV. Zygomycosis in the 1990s in a tertiary-care cancer center. Clin Infect Dis 2000; 30:851-6. 5. Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34:909-17. 6. Neofytos D, Horn D, Anaissie E, et al. Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis 2009; 48:265-73. 7. Bitar D, Van Cauteren D, Lanternier F, et al. Increasing incidence of zygomycosis (mucormycosis), France, 1997-2006. Emerg Infect Dis 2009; 15:1395-401. 8. Prabhu RM, Patel R. Mucormycosis and entomophthoramycosis: a review of the clinical manifestations, diagnosis and treatment. Clin Microbiol Infect 2004; 10(suppl 1):31-47. 9. Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. Clin Microbiol Rev 2000; 13:236-301. 10. Ruping MJ, Heinz WJ, Kindo AJ, et al. Forty-one recent cases of invasive zygomycosis from a global clinical registry. J Antimicrob Chemother 2010; 65:296-302. 11. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007; 356:335-47. 12. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347:408-15. 13. Cordonnier C, Rovira M, Maertens J, et al. Voriconazole for secondary prophylaxis of invasive fungal infections in allogeneic stem cell transplant recipients: results of the VOSIFI study. Haematologica 2010; 95:1762-8. 14. Wingard JR, Carter SL, Walsh TJ, et al. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood 2010; 116:5111-8. 15. Greenberg RN, Mullane K, van Burik JA, et al. Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother 2006; 50:126-33. 16. Ross M, Schmidt GM, Niland JC, et al. Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prevention of acute graftvs.-host disease: effect on chronic graft-vs.-host disease and long-term survival. Biol Blood Marrow Transplant 1999; 5:285-91.

Clinical Lymphoma, Myeloma & Leukemia October 2013

- 627

Emergence of Cunninghamella, an Invasive Mold 17. Baron F, Sandmaier BM, Storer BE, et al. Extended mycophenolate mofetil and shortened cyclosporine failed to reduce graft-versus-host disease after unrelated hematopoietic cell transplantation with nonmyeloablative conditioning. Biol Blood Marrow Transplant 2007; 13:1041-8. 18. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/ Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46:1813-21. 19. Chayakulkeeree M, Ghannoum MA, Perfect JR. Zygomycosis: the re-emerging fungal infection. Eur J Clin Microbiol Infect Dis 2006; 25:215-29. 20. Malani AN, Kauffman CA. Changing epidemiology of rare mould infections: implications for therapy. Drugs 2007; 67:1803-12. 21. Gonzalez CE, Rinaldi MG, Sugar AM. Zygomycosis. Infect Dis Clin North Am 2002; 16:895-914, vi. 22. Greenberg RN, Scott LJ, Vaughn HH, Ribes JA. Zygomycosis (mucormycosis): emerging clinical importance and new treatments. Curr Opin Infect Dis 2004; 17: 517-25. 23. Kontoyiannis DP, Marr KA, Park BJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis 2010; 50:1091-100. 24. Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh TJ, Kontoyiannis DP. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis 2012; 54(suppl 1):S23-34. 25. Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005; 41:634-53. 26. Sivakumar S, Mathews MS, George B. Cunninghamella pneumonia in postbone marrow transplant patient: first case report from India. Mycoses 2005; 48:360-2. 27. Garbino J, Myers C, Ambrosioni J, Gumy-Pause F. Report of a successful treatment of pulmonary Cunninghamella bertholletiae infection with liposomal amphotericin and posaconazole in a child with GVHD and review of the literature. J Pediatr Hematol Oncol 2010; 32:85-7. 28. Garey KW, Pendland SL, Huynh VT, Bunch TH, Jensen GM, Pursell KJ. Cunninghamella bertholletiae infection in a bone marrow transplant patient: amphotericin lung penetration, MIC determinations, and review of the literature. Pharmacotherapy 2001; 21:855-60. 29. Darrisaw L, Hanson G, Vesole DH, Kehl SC. Cunninghamella infection post bone marrow transplant: case report and review of the literature. Bone Marrow Transplant 2000; 25:1213-6. 30. Garcia-Vidal C, Upton A, Kirby KA, Marr KA. Epidemiology of invasive mold infections in allogeneic stem cell transplant recipients: biological risk factors for infection according to time after transplantation. Clin Infect Dis 2008; 47:1041-50.

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31. Bow EJ. Invasive fungal infection in haematopoietic stem cell transplant recipients: epidemiology from the transplant physician’s viewpoint. Mycopathologia 2009; 168:283-97. 32. Leithauser M, Kahl C, Aepinus C, et al. Invasive zygomycosis in patients with graft-versus-host disease after allogeneic stem cell transplantation. Transpl Infect Dis 2010; 12:251-7. 33. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis 2008; 47:503-9. 34. Simitsopoulou M, Georgiadou E, Walsh TJ, Roilides E. Cunninghamella bertholletiae exhibits increased resistance to human neutrophils with or without antifungal agents as compared to Rhizopus spp. Med Mycol 2010; 48: 720-4. 35. Petraitis V, Petraitiene R, Antachopoulos C, et al. Increased virulence of Cunninghamella bertholletiae in experimental pulmonary mucormycosis: correlation with circulating molecular biomarkers, sporangiospore germination and hyphal metabolism. Med Mycol 2013; 51:72-82. 36. Hata DJ, Buckwalter SP, Pritt BS, Roberts GD, Wengenack NL. Real-time PCR method for detection of zygomycetes. J Clin Microbiol 2008; 46:2353-8. 37. Rickerts V, Mousset S, Lambrecht E, et al. Comparison of histopathological analysis, culture, and polymerase chain reaction assays to detect invasive mold infections from biopsy specimens. Clin Infect Dis 2007; 44:1078-83. 38. Dannaoui E, Meletiadis J, Mouton JW, Meis JF, Verweij PE. In vitro susceptibilities of zygomycetes to conventional and new antifungals. J Antimicrob Chemother 2003; 51:45-52. 39. Almyroudis NG, Sutton DA, Fothergill AW, Rinaldi MG, Kusne S. In vitro susceptibilities of 217 clinical isolates of zygomycetes to conventional and new antifungal agents. Antimicrob Agents Chemother 2007; 51:2587-90. 40. van Burik JA, Hare RS, Solomon HF, Corrado ML, Kontoyiannis DP. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis 2006; 42:e61-5. 41. Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother 2009; 53: 24-34. 42. Ibrahim AS, Gebremariam T, Schwartz JA, Edwards JE Jr, Spellberg B. Posaconazole mono- or combination therapy for treatment of murine zygomycosis. Antimicrob Agents Chemother 2009; 53:772-5. 43. Mousset S, Bug G, Heinz WJ, Tintelnot K, Rickerts V. Breakthrough zygomycosis on posaconazole prophylaxis after allogeneic stem cell transplantation. Transpl Infect Dis 2010; 12:261-4. 44. Spellberg B, Walsh TJ, Kontoyiannis DP, Edwards J Jr, Ibrahim AS. Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 2009; 48:1743-51.