Mucormycosis (Zygomycosis) Workup

Updated: Jul 11, 2017
  • Author: Philip J McDonald, MD; Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD  more...
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Workup

Approach Considerations

Timely diagnosis is paramount in cases of mucormycosis. [27] Persons with suspected rhinocerebral disease should undergo emergent computed tomography (CT) imaging of the paranasal sinuses and an endoscopic examination of their nasal passages with biopsies of any suggestive lesions. The diagnosis of mucormycosis is established by obtaining a biopsy specimen of the involved tissue, and frozen tissue samples should be immediately evaluated for signs of infection. Tissue should also be sent for routine pathology examination and cultures. Swabs of tissue or discharge are unreliable.

For pulmonary disease, a bronchoalveolar lavage (BAL), biopsy, or both may assist in the diagnosis.

For cutaneous disease, a skin biopsy for pathology and culture should be obtained.

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Laboratory Tests

A complete blood cell (CBC) count should be obtained to assess for neutropenia. A chemistry panel that includes blood glucose, bicarbonate, and electrolytes is useful to monitor homeostasis and direct correction of acidosis. An arterial blood gas (ABG) study can help determine the degree of acidosis and guide corrective therapy.

Iron studies may be indicated to assess the presence of iron overload as shown by high ferritin levels and a low total iron-binding capacity.

In cases of central nervous system (CNS) involvement, cerebrospinal fluid (CSF) findings may include elevated protein levels and a modest mononuclear pleocytosis. CSF cultures are typically sterile. A CT scan should precede a lumbar puncture to assess for evidence of elevated intracranial pressure, which could lead to herniation.

Blood cultures can be obtained; however, they are usually negative despite the angioinvasive nature of the organism. Blood cultures may be useful to detect bacteremia in addition to Mucorales infection. One study of pulmonary mucormycosis identified concurrent bacteremia as an independent predictor of 28-day mortality. [23] There are no specific biomarkers to identify mucormycosis. Bronchoalveolar lavage (BAL) of fluid culture has a low yield, with a sensitivity of 20%-50%. Antigen tests (beta-D-glucan or galactomannan) are not useful for detecting this infection. [14]

The use of quantitative polymerase chain reaction (qPCR) for detection of circulating DNA from common Mucorales species (Lichtheimia species, Rhizomucor species, and Mucor/Rhizopus species), while not yet commercially available, has been described and appears promising for the early diagnosis of mucormycosis in high-risk patients. [28, 29] In a retrospective analysis of 44 cases, qPCR identification was fully concordant with that of culture. Assay positivity was observed at an average of 9 days, at least 2 days prior to positive imaging findings. Development of PCR negativity after treatment was associated with higher survival rates (48% vs 4%), suggesting that this modality could eventually be used for treatment monitoring. [30]

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Radiologic Studies

Imaging should be used to investigate areas of suspected mucormycosis. Because subclinical disease may be present, a thorough history and physical examination are recommended in addition to imaging (CT) of the brain, sinuses, chest, and abdomen. [31]

Rhinocerebral infections

Plain films may show sinus involvement with mucosal thickening, air-fluid levels, and/or bony erosions. [22]

Head and facial CT imaging should be used as the initial investigation in rhinocerebral infections. CT scans may show sinusitis of the ethmoid and sphenoid sinuses, as well as orbital and intracranial extension. As the disease progresses, bony erosion may occur and the infection may spread into the brain or orbits. In addition, because mucormycosis organisms have a predilection for vascular involvement, thromboses of the cavernous sinus or internal carotid artery may occur. [32] All of the areas of involvement must be understood in order to plan the extent of surgical debridement.

Magnetic resonance imaging (MRI) of the facial sinuses and brain is superior to a CT scan in assessing the degree of tissue invasion and need for ongoing surgery.

Pulmonary disease

While chest radiography is often the initial test performed, its sensitivity and specificity for mucormycosis are low. Nonenhanced high-resolution CT scanning is the imaging modality of choice. [14] The most common findings include pleural effusion, nodules, consolidation, and ground-glass opacities. [23] With disease progression, consolidation can become multilobar. The reverse halo sign (ie, a nodule with central ground-glass opacity and a ring of peripheral consolidation) strongly suggests pulmonary mucormycosis and is rarely seen in invasive aspergillosis. [33] The halo sign (ie, a nodule surrounded by ground-glass opacity) represents a lung infarct surrounded by alveolar hemorrhage; it is associated with invasive mold infections but can be present in bacterial or viral infections and noninfectious lung disease (eg, Wegener granulomatosis, sarcoidosis, malignancy). [14] Other findings such as the air crescent sign and hypodense sign are less specific and may occur in later stages. See the images below.

Chest computed tomography (CT) scan showing pulmon Chest computed tomography (CT) scan showing pulmonary mucormycosis with left basal consolidation and widespread nodules due to Rhizopus oryzae infection. The patient was receiving cytotoxic chemotherapy for myelodysplastic syndrome and had iron overload from numerous blood transfusions.
Chest computed tomography (CT) scan showing pulmon Chest computed tomography (CT) scan showing pulmonary mucormycosis with left basal consolidation and widespread nodules due to Rhizopus oryzae infection. The patient was receiving cytotoxic chemotherapy for myelodysplastic syndrome and had iron overload from numerous blood transfusions. This CT scan of the patient shows resolution of pulmonary mucormycosis after 5 months of antifungal treatment.

Gastrointestinal disease

In gastrointestinal (GI) disease, abdominal CT scans may show a mass associated with the GI tract. Esophagogastroduodenoscopy (EGD) may show areas of tissue necrosis amenable to biopsy.

Central nervous system

CT scanning or MRI of the central nervous system may reveal abscesses (especially in the setting of intravenous drug use) or extension of rhinocerebral disease into the brain. Cavernous and, less commonly, sagittal sinus thrombosis may also be seen. See image below.

Brain MRI (sagittal view) in a patient with uncont Brain MRI (sagittal view) in a patient with uncontrolled diabetes who presented with progressive right eye pain and facial swelling. He underwent multiple surgeries to control rhinocerebral Mucor infection, including partial right frontal lobectomy and right orbital exenteration. He was treated with amphotericin B and his diabetes mellitus was controlled. The disease did not progress, and long-term isavuconazole therapy was initiated for salvage/maintenance therapy.
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Biopsy and Histologic Features

Biopsy of the involved tissue is the most critical means of establishing a diagnosis of mucormycosis. A rapid histologic assessment of a frozen tissue section should be performed in order to promptly institute surgical and medical management for the infection.

Biopsy of necrotic tissue

Biopsy of necrotic tissue may be obtained from nasal, palatine, lung, cutaneous, gastrointestinal (GI), or abscess wall site.

Stains of fixed tissues with hematoxylin and eosin (H&E) or specialized fungal stains, such as Grocott methenamine-silver (see the following image) or periodic acid-Schiff (PAS) stains, show pathognomonic broad (typically 6- to 25-µm diameter), irregular, ribbonlike, nonseptate (or sparsely septate) hyphae with irregular branching occurring at 45-90º. [34] Vascular invasion and necrosis are the characteristic consequences of the infective process. Thus, neutrophil infiltration, vessel invasion, and tissue infarction are often observed. A granulomatous reaction may also be seen.

Histologic findings from an immunocompetent man wh Histologic findings from an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Findings show the typical Mucorales hyphae on Grocott methenamine-silver staining. The hyphae are the dark structures with budlike, right-angle hyphae. Courtesy of A Allworth, MD, Brisbane, Australia.

Culture of biopsy samples is generally required to determine the species of Mucorales. Do not crush or grind the specimen, because the nonseptate hyphae are prone to damage. Growth usually occurs in 2-3 days. The genus and species are determined via examination of the fungal morphology (ie, the presence and location of the rhizoids). Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) can also provide rapid and accurate identification at the species level but requires a reference database. 18s ribosomal RNA (rRNA) sequencing may provide genus-level identification, even if tissue damage precludes fungal growth. [14]

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