Mucormycosis in Transplant Recipients

Authors: Thomas J. Walsh, M.D., Samuel Shoham, M.D., Emmanuel Roilides, M.D., Ph.D

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MYCOLOGY

The term “zygomycosis” has now been replaced by “mucormycosis.” “Zygomycosis” was originally introduced to encompass both mucormycosis and entomophthoramycosis, as infectious processes. However, because of recent advances in molecular phylogenetic analyses, the class name Zygomycetes has been replaced by Glomeromycetes. The class of Zygomycetes was found to be polyphyletic, meaning that some organisms were phylogenetically unrelated. Thus, all agents of mucormycosis have been placed under the subphylum Mucormycotina (order Mucorales), while the agents of entomophthoramycosis are now assigned to the subphylum Entomophthoramycotina (order Entomophthorales). As the order Mucorales is monophyletic (composed of phylogenetically related organisms) and unlikely to change in its nomenclature, the term “mucormycosis” will ultimately be more enduring. Similarly, as the term "Zygomycetes" no longer exists, the disease name “zygomycosis” has become obsolete and has been replaced by “mucormycosis.”

EPIDEMIOLOGY OF RISK FACTORS

Mucormycosis is an uncommon but lethal infection in a wide range of hosts. Common clinical settings for mucormycosis include diabetes (type I and type II) and hematological malignancy (12, 13). Other increasingly recognized patient populations at risk for mucormycosis include those with hematological malignancies and hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (21). Pharmacological immunosuppression caused by corticosteroids, chemotherapy-induced neutropenia, immunosuppressive agents and immunomodulatory monoclonal antibodies increase the risk for development of mucormycosis. Among solid organ transplant recipients, those who receive intense immunosuppression for prevention of graft rejection have heightened risk for development of mucormycosis.

Singh and colleagues in a prospective, matched case-control study further advanced our understanding of the risks for development of mucormycosis in solid organ transplant recipients (23). Renal failure, diabetes mellitus, and previous receipt of voriconazole and/or caspofungin were significantly associated with a higher risk of mucromycosis. Whereas, tacrolimus was associated with a reduced risk of mucormycosis. Liver transplant recipients had a greater probability of developing disseminated infection; they also developed mucormycosis significantly earlier (median of 0.8 months) after transplantation than did other solid organ transplant recipients (median of 5.7 months).

CLINICAL MANIFESTATIONS PERTINENT TO TREATMENT

Mucormycosis in solid organ transplant recipients may present as bronchopneumonia, nodular pulmonary infiltrates, sinusitis, periorbital cellulitis, focal neurological deficits, cutaneous lesions, surgical wound infection, and gastrointestinal perforation (17). The locations of infection vary according to the type of host. Roden et al found that the most common sites of mucormycosis in 61 solid organ transplant recipients were the lower respiratory tract (37%), cutaneous lesions (16%), rhinocerebral infection (16%), sinus disease (15%), gastrointestinal infection (7%), disseminated disease (2%), and other less common sites (7%) (21).

A recent study of pulmonary mucormycosis from the Zygomycosis Transplant Study Group found that among 58 solid organ transplant recipients with mucormycosis, lower respiratory tract infection was documented in 53% and developed a median of 5.5 months post-transplantation (27). Pulmonary mucormycosis was the most common manifestation in solid organ transplant recipients with mucormycosis. Approximately three fourths of the patients had mucormycosis limited to the lungs and the remaining fourth had pulmonary disease as part of disseminated mucormycosis. Pulmonary disease presented most frequently as consolidation/mass lesions (29.0%), nodules (25.8%) and cavities (22.6%).

Pulmonary mucormycosis may radiologically resemble the features of invasive pulmonary aspergillosis. While multiple pulmonary lesions and pleural effusions may occur more frequently in patients with pulmonary mucormycosis than in those with invasive pulmonary aspergillosis, these changes are not specific. Similarly, sinusitis, focal neurological deficits, and cutaneous lesions are also not specific. Hence, a microbiological or histological diagnosis is critical in order to establish the presence of mucormycosis.

LABORATORY DIAGNOSIS

As the definitive diagnosis of mucormycosis carries specific therapeutic implications for the use of amphotericin B, detection of the causative organism in tissue, bronchoalveolar lavage fluid (BALF) and other fluids (other than blood) by direct examination or by culture is important (17).

Specimens are submitted where appropriate to both clinical microbiology, cytopathology, and histopathology laboratories. Direct microscopic examination is accomplished in clinical microbiology laboratories by examination of wet mounts, which may be further enhanced using fluorescent dyes that bind to the fungal cell wall. Tissue or BALF submitted to a pathology laboratory is examined where appropriate by cytology and/or histology.

Mucormycotina in tissue, bronchoalveolar lavage fluid or other fluids appear as broad irregularly branching non-septate or sparsely septate hyphae. The organism may show considerable distortion. Although classically described as “right-angled,” the branching is best described as “non-dichotomous.” However, direct examination may not be conclusive and where possible culture of the organism is preferred.

Culture of the organism permits morphological identification of species, which may carry valuable therapeutic, prognostic and epidemiological implications. Availability of the isolate permits determination of in vitro susceptibility to antifungal agents. While interpretive breakpoints have not been determined for amphotericin B, an off-scale reading (e.g., >8 μg/ml) suggests a poor response to polygene antifungal therapy. Culture of the submitted specimen also may allow for detection of mixed infections, such as those associated with Aspergillums spp.

Molecular diagnostic tools, such as PCR, for detection of Mucormycotina from clinical specimens are promising but currently investigational. By comparison, the use of direct sequencing of DNA extracted from organisms grown on conventional media is applied in some laboratories and may allow for a definitive species diagnosis.

PATHOGENESIS

Sporangiospores are produced by the mycelial form of the organism in the external environment and are inhaled into the upper and lower respiratory tract. Sporangiospores also may contaminate surgical wounds or be traumatically inoculated into the skin. Inhaled spornagiospores may inoculate the paranasal sinus structures or the lower respiratory tract. If sporangiopsores are not cleared by phagocytosis, germination into hyphae may ensue with subsequent invasion into subepithelial tissues in the sinuses and pulmonary vasculature in the lungs.

In patients undergoing lung transplantation, the tracheobronchial anastigmatic site is particularly vulnerable to adhesion by spornagiospores and hyphal invasion. Angioinvasion by hyphal elements of Mucormycotina may then result in thrombosis, ischemia and infarction. The clinical manifestations of this pathophysiological process are reflected by sino-orbital, rhinocerebral, or pulmonary necrotizing infection with angioinvasive organisms typically observed in biopsied tissue.

Innate immunity is a critical component of host defense against infections caused by medically important Mucormycotina. Pulmonary alveolar macrophages prevent germination of sporangiospores into hyphae by phagocytosis and non-oxidative killing of the sporangiospores. Neutrophils mediate hyphal damage through oxidative and non-oxidative mechanisms. Chemotherapy-induced neutropenia and corticosteroid-induced immunosuppression increase the risk for development of mucormycosis. Diabetes mellitus also increases the risk of mucormycosis through several mechanisms: hyperglycemia, metabolic acidosis and glycosylation of iron binding proteins that lead to increased availability of iron. Increased availability of iron also may occur as the result of mobilization of iron by deferoxamine, multiple transfusions in hematological malignancies, or chronic hemolysis as in hemoglobinopathies. For solid organ transplant recipients, corticosteroid-induced immunosuppression and diabetes mellitus represent important pathophysiological conditions where mucormycosis ensue.

ANTIFUNGAL THERAPY

Principles of Treatment

The foundation of primary treatment of mucormycosis is based upon four components: (1) early diagnosis and rapid initiation of therapeutic interventions, (2) antifungal chemotherapy, (3) reversal of immunosuppression and, where applicable, (4) surgical resection. Amphotericin B is the drug of choice for treatment of mucormycosis. However, amphotericin B may be relatively ineffective in a persistently immunocompromised host and in treatment of extensively infarcted tissue in which reduction of immunosuppression and initiation of surgical resection, respectively, are warranted.

Antifungal Chemotherapy

Amphotericin B belongs to the chemical class of polyenes, which exert their antifungal effect through direct interaction with the ergosterol of the fungal cell membranes. Amphotericin B is available in the deoxycholate formulation (DAMB) and as lipid formulations. The available lipid formulations consist of liposomal amphotericin B (LAMB), amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion (ABCD). The lipid formulations of amphotericin B are less nephrotoxic than DAMB (29, 30). Laboratory animal studies and non-comparative clinical observations also indicate that the lipid formulations of amphotericin B are effective in treatment of mucormycosis (10, 22, 29). However, there are no randomized studies between DAMB and lipid formulations of amphotericin B in treatment of mucormycosis. The known antifungal efficacy and reduced nephrotoxicity of lipid formulations of amphotericin B warrant that these agents be used as first line agents in solid organ transplant recipients with mucormycosis.

Table 1 summarizes dosage ranges of the antifungal agents for treatment of mucormycosis. Dosages for pediatric patients may be different from those of adults in order to achieve comparable levels of plasma and tissue exposure similar to those of adults (3). The optimal dosages of amphotericin B and its lipid formulations are not well defined. As a note of caution, selection of the highest dosage possible does not necessarily result in a more favorable pharmacodynamic outcome compared to a lower and less toxic dosage. Selection of a dosage is based upon published reports as well as careful assessment of individual patient tolerability of adverse effects, particularly nephrotoxicity. The use of DAMB in solid organ transplant recipients receiving calcineurin inhibitors increases the risk of dose-dependent renal impairment. A loss of renal function in immunocompromised patients is associated with increased morbidity and mortality. Where possible, a lipid formulation of amphotericin B is preferable to DAMB. Thus, antifungal therapy with amphotericin B is administered with the combined objectives of eradication of mucormycosis and preservation of renal function.

Lipid formulations of amphotericin B are preferred over DAMB in order to preserve renal function for primary treatment of mucormycosis in solid organ transplant recipients. As there are no comparative studies for treatment of mucormycosis, selection of a particular lipid formulation of amphotericin B is usually dictated by the agent that is available in a given institution’s formulary. Although DAMB may cost less per dose in comparison to all other formulations, protection of renal function in a solid organ transplant recipient carries higher priority and warrants the use of a lipid formulation of amphotericin B (15).

While duration of antifungal therapy is not well defined for mucormycosis, several principles can be applied in rationally determining length of therapy. As a general principle, antifungal therapy is continued until resolution of lesions or stabilization of lesions. Antifungal therapy also is continued during the course of neutropenia and throughout immunosuppressive courses of corticosteroids. The use of cyclosporine A, tacrolimus, or sirolimus alone is not sufficiently immunosuppressive to warrant the continuation of antifungal chemotherapy. Thus, in the absence of a clinical trial, the duration of antifungal therapy should be individualized.

Combination antifungal chemotherapy for primary treatment of mucormycosis is investigational. This subject of combination antifungal chemotherapy was recently reviewed in detail elsewhere (26, 31). Laboratory animal data, case reports and case series indicate that echinocandins or deferasirox in combination with lipid formulations of amphotericin B improve antifungal efficacy (26). Randomized comparative clinical trials are needed to further define the role of combination therapy for primary therapy of mucormycosis.

Reversal of Immunosuppression

Reversal of immunosuppression is a critical factor in the successful outcome of management of mucormycosis. The dosages of methylprednisolone or prednisone are reduced to the lowest levels possible while ensuring preservation of graft. Substitution of corticosteroids by other immunosuppressive agents, such as calcineurin inhibitors, mycophenolate, alemtuzumab, dacluzimbab and infliximab may further improve outcome. For patients with diabetes mellitus, control of hyperglycemia and metabolic acidosis reduces the conditions favoring growth of the organism. Neutropenia, which is uncommon in solid organ transplant recipients, in relation to immunosuppressive therapy is usually self-limiting. Persistent neutropenia may be ameliorated or reversed by use of GCSF or GMCSF (8). One also may successfully treat patients with deep visceral mucormycosis through repeated cycles of chemotherapy-induced neutropenia and immunosuppression (32). Profound persistent but reversible neutropenia may be treated by granulocyte transfusions (18); albeit, this modality is seldom necessary in solid organ transplant recipients.

Surgical Resection

Surgical wounds, sinuses and lungs are commonly infected sites for which surgery may be indicated. Full debridement of wounds to clean margins reduces residual fungal burden, removes necrotic tissue and allows for development of granulation tissue. Skin grafting of large wounds is best achieved with minimal to no detectable viable organism. Surgical management is conducted in concert with antifungal chemotherapy and reversal of immunosuppression (5, 16).

The objective of surgical management of sinus and sino-orbital infection is to remove necrotic tissue, reduce residual fungal burden, prevent extension into the cranial cavity, preserve oculomotor function, and protect vision. Extensive surgical exenteration of the craniofacial structures is increasingly giving way to a more conservative approach while optimizing host response and antifungal chemotherapy.

Resection of pulmonary lesions also may reduce residual fungal burden and potentially prevent dissemination. Nonetheless, pulmonary mucormycosis may be treated with antifungal chemotherapy and reversal of immunosuppression without surgical resection. The decision for surgical resection of pulmonary lesions should be individualized to consider several factors: size of lesions, location (e.g. proximity to great vessels and pericardium), penetration into the chest wall, and medical status to tolerate surgery. Thoracoscopic surgery may remove peripheral lesions without the need of thoracotomy. As amphotericin B and its lipid formulations may not achieve sufficient microbicidal concentrations within the pleural space, documented zygomycotic empyema warrants closed chest tube drainage in addition to systemic antifungal therapy (14).

Epidemiology of Outcome

Almyroudis and colleagues recently reviewed the published literature of mucormycosis in solid organ transplant recipients (2). The overall mortality of mucormycosis in this review was 49%. Rhino-sino-orbital disease had the best prognosis while rhinocerebral and disseminated disease had the highest mortality of 93%. Favorable outcome was associated with surgically accessible disease and the combination of early surgical intervention with administration of amphotericin B.

Among the patients reported by Singh and associates in their prospective, matched case-control study, treatment success rate, as defined by complete or partial response, was 60% (23). Renal failure and disseminated disease were independent factors predictive of treatment failure. Surgical resection and treatment with LAMB were each highly associated with successful treatment outcome.

Salvage Treatment

Strategies for salvage therapy have been reviewed in detail elsewhere. These approaches are summarized in Table 2. These approaches are based upon in vitro data, laboratory animal studies, case reports and/or case series. There are no comparative clinical trials for these modalities.

Posaconazole

For patients with mucormycosis which is refractory to or who are intolerant of amphotericin B, posaconazole has been used as salvage therapy for patients with mucormycosis refractory to or intolerant of amphotericin B treatment (9, 28). The favorable responses in patients for salvage therapy contrast with several laboratory animal studies that do not demonstrate activity greater than or equal to that of amphotericin B. The current data indicate that there is no benefit to combination therapy with amphotericin B. For seriously ill patients, the challenge of attaining adequate serum concentrations warrants therapeutic drug monitoring to ensure bioavailability. Development of the parenteral formulation of posaconazole is important to further utilizing the potential benefits of this antifungal triazole.

Deferasirox

Deferasirox is an orally administered iron chelator that is licensed for the treatment of iron overload among patients with transfusion-dependent anemia. Deferasirox, which is fungicidal in vitro against Mucorales, deprives the organism of iron. The agent is synergistic with LAMB in experimental marine mucormycosis. Deferasirox was reported as salvage therapy for a patient with rhinocerebral mucormycosis that was unresponsive to LAMB (19).

A study of deferasirox administered for mean duration of 14 days (range, 7 to 21) at 5 to 20 mg/kg of body weight/day in 8 patients with mucormycosis found rashes in two patients but did not identify renal or hepatic injury. Nonetheless, as deferasirox is associated with gastrointestinal symptoms, hepatic transaminase elevation, and renal dysfunction in larger studies of patients with transfusion-associated iron overload, close monitoring is necessary (24). A pilot randomized trial has been completed that will further increase understanding of the use of this promising modality.

Echinocandins

Addition of an echinocandin to amphotericin B improves antifungal efficacy in animal models and may have benefit in patients (20). Selection of the formulation of amphotericin B and echinocandin are not well defined. Nor is the appropriate dosage of echinocandins in humans that is necessary to achieve this effect characterized. High dosages of echinocandins may antagonize the enhanced antifungal efficacy. In the absence of such data, standard dosages of echinocandins are used (Table 2).

Recombinant Cytokines

Recombinant GMCSF and interferon-γ augment the in vitro antifungal activity of polymorphonuclear leukocytes against medically important Mucormycotina (6). These immunomodulatory molecules have been used alone or in combination in management of invasive mucormycosis in non-neutropenic hosts with mucormycosis (1). However, there is little experience with the use of interferon-γ in solid organ transplant recipients. Such use would be tempered by the potential of interferon-γ for accelerating graft rejection.

Hyperbaric Oxygen

Hyperbaric oxygen therapy in uncontrolled settings has been reported to be useful in management of mucormycosis (4, 11). The possible mechanisms for antifungal activity include improved oxidative metabolism of phagocytic cells and increased oxygen tensions in ischemic tissue. However, the possible contributory role of antifungal chemotherapy, reduction of immunosuppression, augmentation of host defenses, and surgical resection are not well understood. Based upon its known mechanisms of action and its use in approved indications, such as osteoradionecrosis of the mandible, gas gangrene of soft tissue, the most logical applications of hyperbaric oxygen therapy in mucormycosis would be skin, musculoskeletal, and maxillofacial infections.

REFERENCES

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Table 1. Antifungal Agents and Dosages for Primary Treatment of Mucormycosis (Mucormycosis)

Antifungal Agent	Dosage Range in Adult Patients* (mg/kg/day)	Dosage in Pediatric Patients* (mg/kg/day)	Toxicity	Comments
Amphotericin B deoxycholate	.75-1.0	.75-1.0	-Severe nephrotoxicity -Infusion-related toxicity Anemia	Higher dosages are more toxic and not necessarily more effective
Liposomal amphotericin B (AmBisome®)	5-10	5-10	-Reduced nephrotoxicity -Infusion-related toxicity -Uncommon but severe acute infusion-related toxicity	Higher dosages are more toxic and not necessarily more effective
Amphotericin B Lipid Complex (Abele®)	5.0	5.0	-Reduced nephrotoxicity -Infusion-related toxicity	Higher dosages are more toxic and not necessarily more effective
Amphotericin B Colloidal Dispersion (ABCD®)	5.0	5.0	-Reduced nephrotoxicity -Infusion-related toxicity -Infusion-related respiratory distress	Higher dosages are more toxic and not necessarily more effective

*Optimal dosage and duration of antifungal therapy for mucormycosis is not well defined. Dosage and duration of therapy outside of a clinical trial are best assessed individually for each patient.

Table 2. Antifungal Agents and Adjunctive Therapy for Salvage Treatment of Mucormycosis (Mucormycosis)*

Antifungal Agent or Adjunctive Therapy	Dosage Range in Adult Patients*	Dosage in Pediatric Patients*	Toxicity	Comments
Posaconazole	400 mg PO Q12h 200 mg PO Q6h	Investigational	Hepatotoxicity Nausea, vomiting, diarrhea	Used as single agent; no evidence for synergy in combination with amphotericin B
Echinocandins
Caspofungin	70 mg IV loading dose followed by 50 mg/d IV	50 mg/m2/day IV	Hepatotoxicity	Used only in combination with amphotericin B Adjustment in dosage for liver dysfunction
Micafungin	100 mg/d IV	4 mg/kg/day IV	Hepatotoxicity	Used only in combination with amphotericin B Adjustment in dosage for liver dysfunction
Anidulafungin	100 mg/d IV	1.5 mg/kg/d IV	Hepatotoxicity	Used only in combination with amphotericin B No adjustment in dosage needed for liver dysfunction
Posaconazole	400 mg PO Q12h 200 mg PO Q6h	Investigational	-Hepatotoxicity -GI symptoms: nausea, vomiting, and diarrhea	Used as single agent; no evidence for synergy in combination with amphotericin B
Alternative Therapies
Deferasirox (Exjade®)	20 mg/kg/day PO for 2 to 4 weeks	Investigational	-Nephrotoxicity -GI symptoms: nausea and diarrhea	Used only in combination with lipid formulation of amphotericin B
Recombinant cytokines: G-CSF, GM-CSF	G-CSF 5 µg/kg/day SQ or IV GM-CSF 100 to 250 µg/m2	G-CSF 5 µg/kg/day SQ or IV GM-CSF 100 to 250 µg/m2 SQ	Bone pain and arthralgias	GCSF or GMCSF in neutropenic hosts; GM-CSF in non-neutropenic hosts (see text more details)
Granulocyte Transfusions	Approximately ~109 cells/kg	Approximately ~109 cells/kg	-Respiratory distress -Alloimmunization	Indicated for persistently neutropenic patients with documented refractory infection
Hyberbaric oxygen	Refer to comments	Refer to comments		Pressures and duration for management of mucormycosis are not standardized. Management is individualized.