OVERVIEW: What every practitioner needs to know

Are you sure your patient has mucormycosis? What should you expect to find?

Rhinosinusitis, rhino-orbital, and rhinocerebral infections

Although initial symptoms are often indistinguishable from other causes of sinusitis, several factors favor the diagnosis of mucormycosis.

Does your patient have classic risk factors (i.e., uncontrolled diabetes or prolonged hyperglycemia, hematological malignancy/prolonged neutropenia, prolonged high dose corticosteroids, iron overload, allogeneic hematopoetic stem cell transplant recipient with graft versus host disease, or solid organ transplant on chronic immunosuppression)?

Does your patient have a history of previous (prolonged) exposure to Aspergillus-active antifungal agents, particularly voriconazole?
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Does your patient have a clinical presentation of severe sinusitis (pansinusitis or ethmoid involvement)?

Does your patient have necrotic lesions in hard palate or nasal turbinates?
Pulmonary mucormycosis

Does your patient have classic risk factors (i.e., hematological malignancy/prolonged neutropenia, hematopoietic stem cell transplant with graft versus host disease, or receiving high-dose corticosteroids, solid organ transplant recipient on chronic immunosuppression)

Does your patient have a history of previous (prolonged) exposure to Aspergillus-active antifungal agents, particularly voriconazole?

Does your patient have presumed fungal pneumonia despite evidence of adequate serum voriconazole concentrations (i.e., > 2 mcg/mL) and repeatedly negative serum galactomannan or beta-D-glucan test.

Does your patient have any of the following radiographic findings?

Multiple (>10) nodules by CT scan and pleural effusion

Reverse halo sign (ground glass attenuation inside a ring of hemorrhage)

Pulmonary infection suggestive of infection crossing tissue planes (i.e., chest wall cellulitis adjacent to a lung infarct)
Disseminated mucormycosis

In addition to findings listed above, does your patient have evidence of an acute vascular event (e.g., mycocardial infarction, GI bleeding, etc.)
Cutaneous mucormycosis

Does your patient have evidence of recent trauma prior to the infection?

Was your patient involved in an event associated with severe trauma (i.e., motor vehicle accident) or a natural disaster with moving debris (i.e., tornado, tsunami, flood, etc.)

Does your patient have a progressive, necrotizing cutaneous infection unresponsive to broad-spectrum antibiotics?

How did the patient develop mucormycosis? What was the primary source from which the infection spread?

Because Mucorales sporangiospores are widely dispersed in the environment, most cases of mucormycosis develop in immunocompromised hosts following repeated inhalation of fungal spores that are normally harmless in immunocompetent patients. Ideally, severely immunosuppressed patients should refrain from activities that are likely to aerosolize higher inocula of fungal spores (i.e., construction, excavation, vacuuming, cleaning air vents, etc.)

Which individuals are of greater risk of developing mucormycosis?

Patient groups classically at risk for mucormycosis include patients with:

Poorly controlled diabetes mellitus, hyperglycemia, or diabetic ketoacidosis

Hematological malignancies or persistent neutropenia (>4 weeks) following cytoreductive chemotherapy

Hematopoetic stem cell transplant recipients, predominantly higher-risk allogeneic transplant recipients (i.e., haploidentical, T-cell depleted, cord-blood) with graft versus host diseases receiving high-dose corticosteroids for graft versus host disease

Solid organ transplant recipients receiving continuous intensive immunosuppression

Recipients of deferoxamine therapy (less common than previous decades)

Patients with severe burns or trauma are at risk for cutaneous mucormycosis
Otherwise normal hosts can develop disseminated mucormycosis if they inject contaminated solutions (i.e., intravenous drug abusers). Gastrointestinal mucormycosis has been reported in patients who have ingested contaminated food, fermented beverages, or herbal products.

Beware: there are other diseases that can mimic mucormycosis?

Because these infections occur in severely immunosuppressed patients, the initial differential diagnosis for invasive mucormycosis must be correspondingly broad to include other fungal and bacterial pathogens.
Other invasive mold infections produce subacute sinopulmonary syndromes that may be clinically indistinguishable from mucormycosis:

Aspergillosis

Fusariosis

Pseudallescheria complex (includes Scedosporium)

Phaeohyphomycosis (i.e., brown-black molds)

Endemic fungal infections

Cryptococcus (i.e., cryptococcoma)

Advanced (extensive) Pneumocystis jirovecii infection
Bacterial infections that may produce pulmonary findings similar to mucormycosis:

Nocardiosis

Tuberculosis

Pseudomonas aeruginosa, S. aureus

Other resistant bacterial pathogens
Non-infectious diseases can mimic mucormycosis on chest radiographs/ CT scans:

Tumor

Bronchiolitis obliterans organizing pneumonia

What laboratory studies should you order and what should you expect to find?

Complete blood count (CBC) with differential
Liver enzyme tests
Bacterial and fungal cultures from bronchoalveolar lavage/sinus tissue or biopsy specimens and blood
Posaconazole serum trough concentration (if receiving posaconazole)
Voriconazole serum trough concentrations (if receiving voriconazole)
Tests useful for establishing differential diagnosis:

Serum or BAL galactomannan or beta-D glucan (to aid diagnosis of pulmonary aspergillosis)

Serum cryptococcal antigen

Urine and serum antigen assays for histoplasmosis, blastomycosis, and coccidiodomycosis (if history is suggestive of endemic fungal infection)

Pneumocystis DFA or polymerase chain reaction (PCR) from BAL

Quantiferon TB test (however, most experts say this should not be used for diagnosis)

Serum CMV PCR

Results consistent with the diagnosis

No laboratory tests are specifically suggestive of diagnosis beyond cultures from likely infected sites in an “appropriate host” for mucormycosis or histopathology from infected tissue that is consistent with Mucorales infection (gold standard).
Serum-based tests for fungal cell wall antigens (i.e., galactomannan, beta-D-glucan) are not positive in patients with mucormycosis but may be helpful in establishing diagnosis of aspergillosis.
Co-infections with other bacterial pathogens and occasionally other fungi are common. Moreover, culture recovery of Mucorales, even from infected tissue, is poor. Therefore, the lack of fungal growth from tissue specimens or BAL fluid does not rule out the infection.
Biopsy specimens, which are often essential for definitive diagnosis of mucormycosis, may not be feasible in infection sites other than the skin or sinus in a severely pancytopenic patient.

Results that confirm the diagnosis

Histopathological demonstration of broad, ribbon-shaped angio-invasive hyphae in a tissue biopsy specimen sampled from the site of infection, as shown in Figure 1. Growth of Mucorales from normally sterile sites or from BAL fluid in a susceptible host (i.e., allogeneic stem cell transplant patient) with a compatible clinical history (development of sinus disease or pneumonia on voriconazole prophylaxis) and with imaging findings consistent with mucormycosis.

Histology of invasive mucormycosis: (a) hematoxylin and eosin and (b) Grocott’s methenamine silver stain. Arrows indicate hyphal elements.

What imaging studies will be helpful in making or excluding the diagnosis of mucormycosis?

High resolution CT imaging of sinuses/orbits and lungs is helpful. $$
Additionally, CT or MRI imaging should be considered for other sites of suspected involvement in patients with cutaneous or disseminated mucormycosis. $$$$
CT imaging should be repeated serially in patients with suspected mucormycosis or with changes in clinical condition to ascertain infection progression or response to treatment.
($ = 60-125, $$ 125-500, $$$ 500-1,000, $$$$ > 1,000)

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

Infectious Diseases
Ear, Nose, and Throat Specialists (Nasal, sinus endoscopy, biopsy)
Pulmonary (Bronchoscopy, biopsy)
Surgery (Feasibility of surgical debridement/resection of lesions)
Dermatology (skin biopsy)
Microbiology/pathology (alert the lab that mucormycosis is strongly suspected); Biopsy specimens should be processed so as to minimize trauma to the hyphal elements by mincing tissue carefully and not homogenizing or grinding the tissue sample prior to plating.

Key principles of therapy:

Early diagnosis
Reversal or tapering of underlying immunosuppression
Systemic antifungal therapy
Surgical resection or debulking of infected necrotic lesions if feasible
Adjunctive therapies

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Patients should be started on a lipid amphotericin B formulation (possibly with the addition of an echinocandin) at first suspicion of mucormycosis. Delays in the administration of Mucorales-active antifungal therapy are associated with increased potential for spread/dissemination of these aggressive pathogens and increased risk of patient death.

Isavuconazonium sulfate has recently received approval by the FDA for treatment of invasive aspergillosis and invasive mucormycosis. Isavuconazonium sulfate is the water-soluble prodrug of the active triazole isavuconazole. Non-inferiority of isavuconazole to voriconazole for the treatment of Aspergillus infections was demonstrated. The evidence for the efficacy of isavuconazole in mucormycosis was based on historical comparisons. Although questions remain as to relative efficacy of isavuconazole compared to liposomal amphotericin B and its efficacy against individual species, it may be an appropriate choice in patients intolerant of amphotericin B and as salvage therapy. Achieving adequate blood levels with the oral formulation is generally more reliable than with voriconazole and the incidence of adverse drug effects may be lower than with other antifungals.

Although posaconazole may be effective for treatment of some Mucorales infections, it is neither approved nor recommended for use as primary therapy of mucormycosis. Although absorption has been improved with the newer delayed release oral formulation, the lack of an intravenous formulation makes it a less desirable drug for treatment of mucormycosis during the initial acute phases of infection. Patients can be transitioned to posaconazole once infection has stabilized and serum drug levels can be verified.

Management of mucormycosis is generally not stratified by the infecting species. Currently, only four systemic antifungal agents are available for the treatment of mucormycosis: amphotericin B, lipid amphotericin B, posaconazole, isavuconazole and occasionally echinocandins (some will use in combination with lipid amphotericin B formulations) (Table I).

Table I.

Organism	Antifungal
Rhizopus spp.Mucor spp.Cunninhamella spp.Apophysomycesdia spp.Absidia speciesSaksenaea speciesRhizomucor spp.	Lipid Amphotericin B formulationLiposomal amphotericin B (Ambisome)5 mg/kg/day intravenousDaily dosing can be increased to 7.5 mg/kg/day.Amphotericin B lipid complex (Abelcet) 5 mg/kg/dayDosing escalation not recommended due to increased toxicity.
	Echinocandin (optionally used by some clinicians, but only in combination with lipid amphotericin B formulations during initial treatment phase, not as monotherapy)Caspofungin 70 mg day 1, then 50 mg/dayMicafungin 100-150 mg/dayAnidulafungin 200 mg day 1, then 100 mg/day
	TriazolePosaconazole 800 mg/day orally in divided doses (2-4x daily, absorption improved with fatty food and more frequent dosing) with serum drug level monitoring to ensure trough concentrations greater than 1 mcg/mL

Lipid formulations of amphotericin B are preferred over conventional amphotericin B deoxycholate because of the high risk of dose-limiting nephrotoxicity in the populations at risk for mucormycosis (i.e., diabetics, transplant recipients).

2. Next list other key therapeutic modalities.

Control of hyperglycemia/ketoacidosis is critical to reverse physiological conditions that contribute to increase free iron in tissues (acidemia) as well as impair neutrophil function.

Reversal or tapering of immunosuppression (i.e., corticosteroids) improves patient responses to systemic antifungal therapy.

Surgical debridement of infection tissue and/or debulking of necrotic lesions has been associated with improved survival in several case series; however, evidence in this this area is biased by that fact that surgery is more likely pursued in patients with better prognosis of their underlying disease. Nevertheless, radical surgical resections combined with systemic antifungal have been lifesaving when performed early in the course of treatment, particularly in patients with sinus mucormycosis at risk for invasion of the brain.

Controversial or evolving therapies:

Hyperbaric oxygen therapy has been reported effective for cutaneous and sinus mucormycosis and is believed to speed wound healing following surgical resection. The role of this therapy is less well established for pulmonary or disseminated infection and is logistically difficult in severely ill patients.

Granulocyte transfusions have been utilized as a bridge to marrow recovery in patients with persistent neutropenia and invasive fungal infections, including mucormycosis. However, evidence for their effectiveness is limited, and infusions can be associated with an immune-reconstitution-like inflammatory syndrome (IRIS) and worsening lung function. Similarly, adjunctive cytokine treatment (G-CSF, GM-CSF, interferon gamma) has been advocated by some experts to boost impaired host immune responses, but there is little proven efficacy in clinical trials or case series.

Iron chelation with newer agents that cannot be used as xenosiderophores by Mucorales (i.e., deferasirox) has been shown in animal models to exhibit direct antifungal effects through iron starvation and salutary immunostimulatory effects. However, a recent Phase II trial that evaluated adjunctive deferasirox plus liposomal amphotericin B versus liposomal amphotericin B alone (DEFEAT MUCOR study) failed to show a clinical benefit and reported higher mortality rates in patients who received adjunctive deferasirox therapy. The poorer outcomes may be explained by the higher proportion of patients with poorly controlled hematological malignancies in the deferasirox arm.

What complications could arise as a consequence of mucormycosis?

Mucormycosis is associated with mortality rates ranging from 20 to 100%, depending on the severity of underlying host immunosuppression, site of infection or dissemination, and the timeliness of diagnosis and treatment. Generally, cutaneous and sinus mucormycosis are the most readily diagnosed (because of their accessibility for biopsy), most amendable to surgical debridement (although surgical resection is sometimes disfiguring), and associated with the best prognosis.

Rhinocerebral, pulmonary and disseminated mucormycosis are associated with higher mortality rates, and, if not detected early and aggressively treated with systemic antifungal therapy and improvement in the patient’s underlying immunosuppression, will be uniformly fatal.

The site of infection and underlying host factors (immunosuppression) are key prognostic determinants of mucormycosis outcome.
Patients with active hematologic malignancy, allogeneic hematopoietic stem cell transplantation, and disseminated infection have the poorest outcomes with 30-60% of most patients dying within 12 weeks of diagnosis.
Early diagnosis, correction of underlying immunosuppression, combined with aggressive multi-faceted treatment (i.e., systemic antifungal therapy, surgery) offers the best opportunity for patient survival.

How do you contract mucormycosis and how frequent is it?

Mucormycosis is primarily acquired in immunocompromised hosts through inhalation of fungal spores from the environment.
Soft-tissue infections may also develop in immunocompetent hosts following surgery, trauma, burns, direct injection, or catheter infections.
Healthcare associated outbreaks of mucormycosis have been linked to contaminated bandages, needles, and tongue depressors used as splints in intravenous cannulation sites in preterm infants. Rare cases of gastrointestinal mucormycosis have been reported following ingestion of non-nutritional substances (pica), fermented porridges or alcoholic drinks, and herbal remedies, contaminated with fungal spores.
Although no clear pattern of seasonality has been described with mucormycosis, outbreaks of respiratory and soft tissue infections have been observed following catastrophic weather events, including tsunamis, hurricanes, tornadoes, or volcanic eruptions. Mucormycosis should be considered in the differential diagnosis of any patient with progressive skin and soft tissue infection unresponsive to antibiotics following trauma during a catastrophic weather event.
Patient risk factors for mucormycosis include:

Poorly controlled diabetes mellitus type I or II

Metabolic acidosis, which results in increased systemic free iron (loss of transferrin iron binding capacity)

High-dose glucocorticoid therapy

Penetrating trauma or burns

Persistent neutropenia (i.e. >4 weeks)

Chelation therapy with deferoxamine in patients on dialysis or chronic transfusion dependence
Mucormycosis has been less commonly reported in patients with renal failure without chelation therapy, malnutrition, low-birth weight infants, or patients with acquired immunodeficiency syndrome.
Mucormycosis cases have significantly increased over the last decade in patient populations classically at risk for opportunistic fungal infections, such as aspergillosis. This population includes patients with hematological malignancy, recipients of hematopoietic stem cell transplantation (HSCT), and patients undergoing solid organ transplantation.
Data from the Centers for Disease Control and Prevention (CDC) Transplant Associated Infection Surveillance Network (TRANSNET), which surveyed 25 U.S. Transplantation Centers from 2001 to 2006, noted a 12-month cumulative incidence of mucormycosis ranging from 0.1 to 0.7 infections per 1000 HSCT transplants during the study period, with a lower cumulative incidence of 0.1-0.2 among solid organ transplant recipients.
The prevalence of mucormycosis in autopsy series has ranged from 1 to 5 cases per 10,000 autopsies, approximately 10- to 50-fold less common than Candida or Aspergillus infection, respectively.
The routine use of voriconazole prophylaxis in many transplant centers has been temporally linked to an increase in mucormycosis cases since 2002. However, other clinical risk factors probably contributed equally to this trend (i.e., prolonged survival after transplant, hyperglycemia and iron overload with frequent transfusions and extended use of high-dose corticosteroids). Mucormycosis should be strongly suspected in any heavily immunosuppressed patient on voriconazole prophylaxis who develops fulminant sinusitis or nodular lung lesions.
Infection control issues:

Patient-to-patient transmission of mucormycosis is unlikely. However, outbreaks or pseudo-outbreaks of healthcare-associated mucormycosis have been reported with contaminated bandages, tongue depressors, and other medical solutions or devices as previously described. Construction, excavation, or cleaning of air ducts may aerosolize large inocula of Mucorales that, when inhaled, have been associated with progressive pulmonary mucormycosis, even in immunocompetent hosts.

Patients with soft tissue mucormycosis often have a history of preceding trauma that resulted in subcutaneous inoculation of fungal spores. Cutaneous mucormycosis has been reported even with minor trauma, including insect bites and tattooing.

Gloves, gown, and masking do not protect against the transmission of mucormycosis.

What pathogens are responsible for mucormycosis?

Mucormycosis is a general term for infections caused by a group of filamentous fungi belonging to the class Glomeromycetes, which, because of recent taxonomic reclassification, has replaced the former class name Zygomycetes. Previously, the term zygomycosis encompassed both agents of mucormycosis and fungi responsible for entomophthoramycosis (an uncommon subcutaneous infection encountered predominantly in the tropics). In the revised classification, all agents of mucormycosis have been placed under the subphylum Mucormycotina, whereas agents of entomophthoramycosis are now classified under the subphylum Entomophthoramycotina. Because most fungal pathogens associated with mucormycosis are also in the order Mucorales, the disease name of mucormycosis is now considered more taxonomically and clinically accurate than the previously used (and now obsolete) term zygomycosis.

Mucorales are ubiquitous throughout the environment and are commonly found in decaying organic matter, soil, compost, and animal excreta. Mucorales characteristically produce large, ribbon-like hyphae with irregular diameter and only occasional septae, hence, their frequent characterization in tissue as aseptate fungi. Identification of Mucorales is confirmed during culture when characteristic, saclike fruiting structures (sporangia) that produce internally yellow or brown spores (sporangiospores) are observed. These sporangiospores, which range from 3 to 11 micrometers in diameter, are easily aerosolized and cause infections in susceptible hosts when inhaled or introduced through the cutaneous or percutaneous route.

In a review of more than 900 reported human cases of mucormycosis, Roden and colleagues found the majority of human mucormycosis cases were caused by fungi classified under the following genera:

Rhizopus species (47%)
Mucor species (18%)
Cunninghamella species (7%)
Apophysomyces species (5%)
Absidia species (5%)
Saksenaea species (5%)
Rhizomucor pusillus (4%)

Other genera belonging to Mucorales represented less than 3% of culture confirmed cases.

How do these pathogens cause disease?

Innate immune responses in healthy hosts typically clear sporangiospores before infection can be established.
To establish infection, spores must overcome killing by mononuclear and polymorphonuclear phagocytes to germinate into hypal forms (the angio-invasive form of the infection). Most inhaled spores can avoid upper host defenses and reach distal alveolar spaces. However, larger spores (>10 micrometers) may lodge in nasal turbinates, predisposing patients to sinusitis, as illustrated in Figure 2.
Patients with hemochromatosis (iron overload) are predisposed to mucormycosis because of the essential role free iron plays in the growth of Mucorales in vivo.
Patients with diabetic ketoacidosis are susceptible to developing rhinocerebral mucormycosis, because serum transferrin has a diminished capacity to bind and sequester free iron as the pH in the bloodstream falls below 7.4.
Historically, patients with severe hemochromatosis or aluminum toxicity received treatment with the chelation agent deferoxamine. However, deferoxamine can be utilized by some Mucorales (Rhizopus) as a xenosiderophore (foreign iron carrier protein) to form a ferrioxamine complex. This complex makes available the iron, which was previously unavailable to the fungus. Thus, deferoxamine therapy is actually associated with increased risk for fulminant mucormycosis.
Unlike deferoxamine, newer iron chelators, such as deferiprone and deferasirox, have not been associated with increased risk for mucormycosis, because they cannot be utilized as a xenosiderophore by Mucorales. In fact, both deferiprone and deferasirox have demonstrated protective effects in experimental and human mucormycosis because of their net iron-starvation effects on the fungus.
Mucorales have an exceptional capacity to invade blood vessels, resulting in hemorrhage and thrombosis of surrounding tissue and tissue necrosis.
Histopathologic examination of infected tissue typically reveals extensive necrosis with diffuse infiltration of polymorphonuclear neutrophils. Many areas with extensive ischemic necrosis demonstrate minimal inflammation despite extensive hyphal invasion. Pyogenic or a pyogranulomatous response without angio-invasion is common in tissue infections of otherwise healthy hosts.

Pathophysiology of sinopulmonary mucormycosis.

What other clinical manifestations may help me to diagnose and manage this disease?

Predisposing conditions and sites of infections are given in Table II.

Table II.

Predisposing condition	Predominant site of infection
Diabetes mellitus	Rhinocerebral, sino-orbital, cutaneous
Malignancy	Pulmonary, sinus, cutaneous, sino-orbital
Hematopoetic stem cell transplantation	Pulmonary, disseminated, rhinocerebral
Solid organ transplantation	Sinus, cutaneous, pulmonary, rhinocerebral, disseminated
Intravenous drug use	Cerebral, endocarditis, cutaneous, disseminated
Deferoxamine therapy	Disseminated, pulmonary, rhinocerebral, cutaneous, gastrointestinal
Trauma	Cutaneous, ocular

Rhinosinusitis, rhino-orbital, and rhinocerebral infections are common manifestations of mucormycosis. Infection is initially localized to the nasal turbinates and paranasal sinuses following inhalation of sporangiospores but rapidly progresses to the orbit (sino-orbital) or brain (rhinocerebral), especially in patients with diabetic ketoacidosis or profound neutropenia.

Initial symptoms of sinus invasion by mucormycosis are indistinguishable from other more common causes of sinusitis. Sinus pain, congestion, headache, mouth or facial pain, otologic symptoms, and hypoosmia and anosmia are common.

Sinus disease often extends into contiguous structures. Maxillary sinus infection extends to the hard palate, nasal cavity, and ethmoid sinus. Sphenoid infection invades the cavernous sinus, contiguous temporal lobe and internal carotid artery in the siphon. Ethmoid sinus disease may invade the face or frontal lobe of the brain but easily crosses the lamina papyracea into the orbit, causing unilateral infection.

Periorbital edema, proptosis, chemosis, and preseptal and orbial cellulitis are early signs of orbital extension. Pain and blurring/loss of vision often indicate the invasion of the globe or optic nerve. Patients with extensive rhino-orbital or rhinocerebral disease may present with trigeminal and facial cranial nerve palsy with invasion of the cavernous sinus. A bloody nasal discharge may be the only sign that infection has invaded through the nasal turbinates into the brain.

Intracranial complications include epidural and subdural abscess, cavernous and, less commonly, sagittal sinus thrombosis. Meningitis is uncommon.

Involved tissues become red, then violaceous, and finally black with thrombosis and tissue necrosis. Necrotic eschars of the nasal cavity and turbinates may be evident with nasal endoscopy. Facial lesions, exophytic or necrotic lesions of the hard palate, are often signs of rapidlyv progressing infection, as illustrated in Figure 3. The absence of lesions does not rule out sinus mucormycosis, as necrotic or hard palate lesions may be present in only 50% of patients.

Non-productive cough is often the only symptom of lung involvement.

Radiographic imaging often suggests severe sinusitis but is not specific for mucormycosis. Patients may also have superimposed bacterial sinusitis or bacterial meningitis following invasion of the dura mater. Computer tomography of the sinuses typically reveals mucosal thickening, air-fluid levels, and boney erosion, as illustrated in Figure 4. Orbital muscle thickening may be detected on CT scan but can be detected earlier by magnetic resonance imaging (MRI).

Severely immunosuppressed patients often present with pansinusitis highly suggestive of an aggressive fungal infection. Therefore, systemic antifungal therapy active against Mucorales (typically a lipid amphotericin B formulation) should be started immediately in severely immunosuppressed patients until surgical exploration of the sinus or biopsy can be performed.

Initial CT and MRI scans are sometimes unremarkable in patients during the initial stages of rhinocerebral mucormycosis but show evidence of rapid infection progression 48-72 hours later. Therefore, serial radiographic imaging is important in patients with suspected mucormycosis or when clinical progression is suspected,

Rhinoscopy or nasal endoscopy should be performed as soon as possible to look for areas of tissue ischemia or necrosis. Biopsies and/or surgical exploration of suspicious lesions should be performed as soon as possible to establish an early definitive diagnosis.

Pulmonary mucormycosis is most commonly encountered in patients with prolonged neutropenia, recipients of hematopoietic stem cell or solid organ transplantation, or patients who have received deferoxamine therapy.

Pulmonary infection may occur in conjunction with sinus infection.

The clinical and radiographic manifestations of pulmonary mucormycosis are indistinguishable from more common molds, such as invasive pulmonary aspergillosis. Therefore, timely diagnosis is critical for patient outcome, as many frontline agents used for invasive aspergillosis (i.e., voriconazole) lack activity against Mucorales. Delays in the administration of Mucorales-active therapy for pulmonary infection by as little as 6 days have been associated with a doubling of patient mortality.

Clinical manifestations of pulmonary mucormycosis are subtle and non-specific, even in later stages of infection. Patients typically present with refractory fever on broad-spectrum antibiotics, nonproductive cough, progressive dyspnea, and pleuritic chest pain.

Mucormycosis can rapidly traverse tissue planes in the lung, including the bronchi, diaphragm, chest wall, and pleura.

Clues that may be suggestive of pulmonary mucormycosis versus aspergillosis in severely immunocompromised patients include severe sinusitis, infection that develops on voriconazole therapy, and repeated absence of detectable Aspergillus galactomannan antigen in the serum or BAL fluid.

Polymicrobial pneumonia is common in patients with pulmonary mucormycosis, which can confound microbiologic diagnosis.

Radiographic presentation of pulmonary mucormycosis is broad, including nonspecific infiltrates, nodular lesions, cavitary lesions, or even diffuse opacities.

High resolution chest CT is the best method for determining the extent of pulmonary mucormycosis.

Thrombosis of pulmonary vessels with fungal invasion often results in wedge-shaped infarcts as illustrated in Figure 5. Halo and air crescent signs are more common in pulmonary aspergillosis; however, reverse halosign (a focal round area of ground glass opacity surrounded by a ring of consolidation) is more common in patients with pulmonary mucormycosis.

Centrally-located cavitating lesions with the air-crescent sign are often associated with increased risk for pulmonary artery erosion and massive hemoptysis.

Pulmonary mucormycosis will rapidly spread to the contralateral lung and distal organs if not promptly treated. Patients typically die from disseminated infection before respiratory failure occurs.

In immunocompetent hosts, pulmonary mucormycosis may present with a slowly progressing pneumonia with pulmonary aneurysms and pseudoaneurysms, bronchial obstruction, or solitary nodules.

Diabetic patients may present with solidary endobronchial infection that has a less fulminant course than pulmonary mucormycosis in the neutropenic or transplant population. Occasionally, these endobronchial lesions obstruct major airways or erode into pulmonary arteries, leading to fatal hemoptysis.

Similar to Aspergillus, Mucorales can form mycetomas in preexisting lung cavities or produce a slowly progressive necrotizing pneumonia and hypersensitivity syndromes. Rhizopus species have been implicated in allergic alveolitis in farm workers and Scandinavian sawmill workers.

Cutaneous mucormycosis is typically the result of direct spore inoculation or exposure to skin already compromised by burn or trauma.

Cutaneous mucormycosis typically begins as erythema and induration of the skin at a puncture site and progresses to necrosis with a black eschar. Cutaneous infections can progress rapidly to involve the deep fascia and muscle layers. Necrotizing fasciitis has been reported in patients with cutaneous mucormycosis and is associated with an extremely poor prognosis.

The skin is a less common site of secondary involvement for disseminated mucormycosis in comparison with other molds (i.e., Aspergillus, Fusarium) that infect neutropenic patients.

Necrotic lesion of the hard palate in patient with rhinocerebral mucormycosis.

CT radiograph demonstrating right-sided sinusitis (arrows) in patients with rhinocerebral mucormycosis.

Large wedge-shaped infarct (arrow) in patient with pulmonary mucormycosis.

How can mucormycosis be prevented?

There is no vaccine against Mucorales.
Recent studies have supported the use of primary mold-active antifungal prophylaxis with posaconazole in high risk populations such as those undergoing treatment for acute leukemia or stem cell transplantation and those with graft versus host disease. While such therapy does appear to decrease the incidence of invasive fungal infection (IFI) and IFI-related mortality, it may also be associated with increased adverse effects and cost.
Secondary antifungal prophylaxis or chronic suppressive therapy should be considered for persistently immunosuppressed patients, and therapy should be intensified during periods of more severe immunosuppression. Anecdotal cases of mucormycosis reactivation in patients with acute leukemias and/or stem cell transplantation have been reported following more than 2 years of continuous treatment and documented response/radiographic clearance on antifungal therapy and tapering immunosuppression. Typically, delayed release posaconazole (300 mg daily administered orally) is the drug of choice because of convenience, but lower doses of every other day lipid amphotericin B (i.e., 3 mg/kg/day or 5 mg/kg 3-4x weekly) has also been used as suppressive therapy.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Because of the relative rarity of mucormycosis, optimal management of the infection is based primarily on expert opinion and evidence from uncontrolled case series. Treatment guidelines have not been published for the management of invasive mucormycosis. An annotated summary of key literature and useful reviews are provided.

Kontoyiannis, DP, Lionakis, MS, Lewis, RE. “Zygomycosis in a tertiary-care cancercenter in the era of Aspergillus-active antifungal therapy: acase-control observational study of 27 recent cases”. J Infect Dis. vol. 191. 2005. pp. 1350-60. (This is a case-control study of mucormycosis in hematological malignancy patients that identified voriconazole pre-exposure as an independent risk factor for infection.)

Neofytos, D, Horn, D, Anaissie, E. “Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Allianceregistry”. Clin Infect Dis. vol. 48. 2009. pp. 265-7. (This is a contemporary epidemiological survey of invasive fungal infections in adult HSCT patients that demonstrated that mucormycosis was the third most common invasive fungal infection and associated with significantly higher mortality than aspergillosis or candidiasis.)

Park, BJ, Pappas, PG, Wannemuehler, KA. “Invasive non-Aspergillus mold infections in the transplant recipients, United States 2001-2006”. Emerg Infect Dis. vol. 17. 2011. pp. 1855-64. (This is a contemporary epidemiological survey of transplant centers that demonstated increasing incidence and high mortality rates of mucormycosis in U.S. Transplant Centers.)

Roden, MM, Zaoutis, TE, Buchanan, WL. “Epidemiology and outcome of zygomycosis: a review of 929 reported cases”. Clin Infect Dis. vol. 41. 2005. pp. 634-53. (This is the largest epidemiological survey of mucormycosis that encompasses all published cases.)

Artis, WM, Fountain, JA, Delcher, HK, Jones, HE.. “A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability”. Diabetes. vol. 31. 1982 Dec. pp. 1109-14. (This is a classic paper that demonstrated the link between free iron availability in diabetic ketoacidotic patients and the pathogenesis of mucormycosis.)

Ma, LJ, Ibrahim, AS, Skory, C. “Genomic analysis of the basal lineage fungus Rhizopus oryzae reveals a whole-genome duplication”. PLoS Genet. 2009. pp. 5e1000549(This source summarizes findings from genomic sequencing of Rhizopus oryzae and possible explanations for the remarkable capacity of the organism for aggressive growth, pathogenesis in humans, and possibly resistance to multiple antifungal classes.)

Chamilos, G, Marom, EM, Lewis, RE, Lionakis, MS, Kontoyiannis, DP.. “Predictors of pulmonary zygomycosis versus invasive pulmonary aspergillosis in patients with cancer”. Clin Infect Dis. vol. 41. 2005. pp. 60-6. (This is a retrospective study that examined clinical and radiographic features that may allow clinicians to distinguish invasive pulmonary mucormycosis from aspergillosis.)

Lass-Florl, C, Resch, G, Nachbaur, D. “The value of computed tomography-guided percutaneous lung biopsy for diagnosis of invasive fungal infection in immunocompromised patients”. Clin Infect Dis. vol. 45. 2007. (This study utilized a unique algorithm of adjunctive diagnostic tests and microscopy (calcoflour staining for septated versus non septated hyphae, Aspergillus galactomannan, and PCR tests) to distinguish Aspergillus infections from Mucorales infection CT-guided lung biopsy specimens.)

Kontoyiannis, DP, Chamilos, G, Hassan, SA, Lewis, RE, Albert, ND, Tarrand, JJ.. “Increased culture recovery of Zygomycetes under physiologic temperature conditions”. Am J Clin Pathol. vol. 127. 2007. pp. 208-12. (This laboratory study suggested growth of Mucorales from tissue samples can be improved if samples are minced, and cultures is performed in microaerophilic conditions at 37°C.)

Andes, D, Pascual, A, Marchetti, O.. “Antifungal therapeutic drug monitoring: established and emerging indications”. Antimicrob Agents Chemother. vol. 53. 2009. pp. 24-34. (This is a comprehensive review on therapeutic drug monitoring with antifungal that includes specific recommendations for posaconazole monitoring in the prophylaxis and treatment of invasive fungal infection.)

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. vol. 47. 008 Aug 15. pp. 503-9. (This is a study in hematological malignancy patients demonstrating that delays in the administration of Mucorales-active antifungal therapy in patients with pulmonary mucormycosis is associated with increased mortality.)

Greenberg, RN, Mullane, K, Van Burik, JA. “Posaconazole as salvage therapy forzygomycosis”. Antimicrobial Agents Chemother. vol. 50. 2006. pp. 126-33.

Ibrahim, A, Gebermariam, T, Fu, Y. “The iron chelator deferasirox protects mice from mucormycosis through iron starvation”. J Clin Invest. vol. 117. 2007. pp. 2649-57. (This is an analysis of the mechanisms by which new generation iron chelators, which cannot be used by Mucorales as xenosiderophores, exhibit anti-mucorales activity in vitro and in vivo.)

John, BV, Chamilos, G, Kontoyiannis, DP.. “Hyperbaric oxygen as an adjunctive treatment for zygomycosis”. Clin Microbiol Infect. vol. 11. 2005. pp. 515-7. (Review of published literature concerning the use of hyperbaric oxygen therapy for mucormycosis and critical analysis.)

Kontoyiannis, DP, Lewis, RE.. “How I treat mucormycosis”. Blood. vol. 118. 2011. pp. 1216-24. (This is a review regarding the evidence and "art" of managing patients with invasive mucormycosis in hematological malignancy patients. The authors provide treatment algorithms for common clinical situations that arise in these populations.)

Reed, C, Bryant, R, Ibrahim, AS, Edwards, J, Filler, SG, Goldberg, R, Spellberg, B.. “Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis”. Clin Infect Dis. vol. 47. 2008. pp. 364-71. (Retrospective study of 41 patients with rhinocerebral mucormycosis that suggested combination of an echinocandin plus lipid amphotericin B formulation are associated with significantly improved clinical success and survival compared to lipid amphotericin B alone.)

Spellberg, B, Ibrahim, AS, Chin-Hong, PV. “The Deferasirox-AmBisome therapy for mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial”. J Antimicrob Chemother. vol. 67. 2012 Mar. pp. 715-22. (A phase II trial of deferasirox adjunctive therapy for mucormycosis, which failed to show a benefit and possibly increased mortality with iron chelation therapy. However, the results may have been skewed by imbalances in the proportion of patients with poorly controlled leukemia enrolled in the deferasirox arm.)

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. vol. 42. 2006. pp. e61-5. (Two studies that summarize clinical experience, safety, and toxicity of using posaconazole for the treatment of invasive mucormycosis.)

Ethier, MC1, Science, M, Beyene, J, Briel, M, Lehrnbecher, T, Sung, L.. “Mould-active compared with fluconazole prophylaxis to prevent invasive fungal diseases in cancer patients receiving chemotherapy or haematopoietic stem-cell transplantation: a systematic review and meta-analysis of randomised controlled trials”. Br J Cancer. vol. 106. 2012 May 8. pp. 1626-37. (A meta-analysis and review of recent studies on the use of mold-active prophylaxis with posaconazole in high-risk groups.)

DRG CODES and expected length of stay

117.7 – Zygomycosis (Phycomycosis or Mucormycosis), Infection by species of Absidia, Basidiobolus, Conidiobolus, Cunninghamella, Entomophthora, Mucor, Rhizopus, Saksenaea

**The original author for this chapter was Dr. Russell Lewis. The chapter was revised by Dr. Sankar Swaminathan.

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Agents of Mucormycosis (Clinical Condition)