Mucormycosis, fusariosis, scedosporiasis, and other invasive mold diseases

Increasing incidence and breakthrough infections.

The overall incidence of mucormycosis-related hospitalizations in the United States doubled from 1.7 per million in 2000 to 3.4 per million persons in 2013. Breakthrough infection in patients receiving voriconazole, which has anti- Aspergillus activity yet no activity against mucormycosis, has been noted more often among patients with mucormycosis than controls and patients with other IMDs. ^, Although there may be some selective effect favoring emergence of non- Aspergillus IMD in patients receiving mold-active antifungal therapy, there has also been substantial growth in the at-risk population and improved survival from other opportunistic infections. For example, some studies have found a stable incidence of mucormycosis over time among hematopoietic stem cell transplant (HSCT) recipients, but an increase in the absolute number of cases corresponding to patients who receive transplants. ^{, ,} Signs or symptoms concerning for an IMD in a patient already receiving a mold-active antifungal agent without mucormycosis coverage (e.g., voriconazole) should increase suspicion for mucormycosis or another rare, potentially antifungal-resistant IMD. Additionally, it is important to maintain consideration of invasive aspergillosis, especially an azole-resistant isolate or an azole-resistant species (e.g., Aspergillus calidoustus ) in the differential diagnosis for breakthrough IMD. Breakthrough IMD could occur because of intrinsic or acquired antifungal resistance, suboptimal antifungal exposure owing to inadequate dosing, nonadherence, high inoculum burden, or host immune factors. Table 25.1 summarizes reported breakthrough IMDs on various antimold prophylaxis agents.

Hematopoietic stem cell transplant.

Table 25.2 summarizes the key epidemiologic features of mucormycosis in HSCT recipients, solid organ transplant (SOT) recipients, and oncology patients. The majority of data are derived from adult studies. Among HSCT recipients in the Transplant-Associated Infection Surveillance Network (TRANSNET) study from 2001 to 2006, mucormycosis represented 77 (8%) of 983 invasive fungal disease (IFD) cases, whereas invasive aspergillosis represented 43% of IFDs. Mucormycosis is more likely to occur in allogeneic HSCT recipients than autologous HSCT recipients. The median time of onset of mucormycosis in the TRANSNET study was 135 days after transplant versus 99 days after transplant for invasive aspergillosis.

Solid organ transplant.

Among primarily adult SOT recipients in the TRANSNET study, mucormycosis represented only 2% of all IFDs versus 19% caused by invasive aspergillosis. Compared with other types of SOT recipients, liver transplant recipients present earlier after transplant and have a higher frequency of disseminated disease; their risk is hypothesized to be related to iron overload. ^, Mucormycosis is rare among pediatric SOT recipients.

Oncology.

Hematologic malignancy (with or without HSCT) is the most common underlying condition reported among adult and pediatric patients with mucormycosis, accounting for 45 to 60% of cases in large series. Patients undergoing therapy for hematologic malignancy often share multiple concurrent risk factors for mucormycosis.

Prognosis and modifying factors.

Mucormycosis is a highly fatal disease; however, specific mortality estimates vary widely depending on the clinical population and duration of follow-up. A recent pediatric case series reported a case fatality rate of 33.3% at last follow-up. Risk factors for death include disseminated disease, hematologic malignancy, HSCT, monocytopenia at diagnosis, and lymphopenia at diagnosis. ^{, ,} In some studies, higher mortality has been noted with infection caused by Cunninghamella species. Favorable prognostic factors include localized cutaneous disease, surgical resection of disease, early amphotericin B–based therapy, and neutrophil recovery. ^{, , ,}

Pulmonary mucormycosis.

The presenting symptoms and signs of pulmonary mucormycosis are similar to those of other pulmonary IMDs. Radiographic findings can include nodules, consolidation, cavitary lesions, and/or wedge-shaped lung infarcts. Despite the clinical similarities, case series evaluating radiographic findings of mucormycosis in patients with hematologic malignancies have identified certain findings more frequently in patients with pulmonary mucormycosis as opposed to pulmonary aspergillosis. These include multiple pulmonary nodules (>10), pleural effusion(s), and the reverse halo sign. The reverse halo sign ( Fig. 25.1 ) is a focal area of ground-glass opacity surrounded by a ring of consolidation; among patients with hematologic malignancies it is strongly associated with mucormycosis. However, there are other potential etiologies of the reverse halo sign, so it should be interpreted based on pretest probability. The reverse halo sign is uncommon in nonneutropenic patients with mucormycosis.

Rhinocerebral mucormycosis.

Different literature sources refer variably to rhino-orbital, sino-orbital, sinus, rhinocerebral, or rhino-orbito-cerebral mucormycosis. In this chapter we use the term “rhinocerebral mucormycosis” to describe infection involving any of the following structures: the palate, the sinuses, the orbit and any adjacent structures, with or without extension via contiguous or hematogenous routes to the brain. Manifestations depend on the specific sites and the extent of disease involvement. Features that distinguish rhinocerebral mucormycosis from rhinocerebral aspergillosis include a propensity to involve the orbit, involvement of the ethmoid sinuses, and pansinusitis. Concurrent pulmonary and rhinocerebral/sinus involvement should also prompt suspicion for mucormycosis as opposed to aspergillosis.

Cutaneous mucormycosis.

Cutaneous lesions seen in mucormycosis can be primary, developing after localized inoculation at sites of trauma, intravascular catheters or adhesive tape, or secondary owing to hematogenous dissemination from another site of disease.

Other forms of mucormycosis.

The gastrointestinal tract is the least commonly involved primary site of mucormycosis; its manifestations are described in Table 25.3 . One exception is in neonatal disease, but the pathogenesis is likely different than mucormycosis in transplant recipients or oncology patients. Mucormycosis can involve any organ or tissue, either via hematogenous dissemination, deep contiguous extension from the primary focus, or inoculation at sites of trauma or surgery. The brain is one of the most common sites involved via hematogenous dissemination.

Diagnostic sampling.

Obtaining clinical samples from the affected site(s) is essential as there are currently no standardized diagnostic biomarkers or other well-validated noninvasive tests to diagnose mucormycosis. Results of serum galactomannan and (1,3)-β-D-glucan tests are usually negative in mucormycosis as these antigens are not released or not released in detectable quantities by the Mucorales. The ideal sample for diagnostic evaluation is tissue from the affected site(s) for histologic verification. Tissue samples are more readily obtainable in the setting of rhinocerebral and cutaneous disease but are challenging to obtain from the lungs. Unfortunately, the lungs are the predominant site of mucormycosis in transplant recipients and oncology patients. Recovery of Mucorales from sputum and bronchoalveolar lavage (BAL) samples is low (25% from BAL in one study); however, BAL may be useful in evaluating for other etiologies of pneumonia in an immunocompromised patient, and experts have suggested higher potential yield in the first 48 to 72 hours from symptom onset. Computed tomography (CT)-guided lung biopsy has shown utility in establishing the diagnosis of pulmonary mucormycosis. Correction of coagulopathy and/or transfusion of platelets may be required to reduce bleeding risk before a patient can undergo biopsy. Correcting any identified coagulopathy is of particular importance in this setting given the angioinvasive nature of these pathogens, which may further predispose the patient to bleeding during or after a biopsy procedure. Although clinicians may be reluctant to pursue invasive procedures, the value of an invasive intervention should be emphasized given its influence on antifungal therapy choice (e.g., different antifungal classes for invasive aspergillosis versus mucormycosis), the likelihood for earlier initiation of appropriate directed therapy, and the opportunity for improved source control with removal of necrotic tissue that might diminish antifungal effectiveness.

Primary diagnostic tests.

Direct microscopy of clinical samples with an optical brightener such as calcofluor white can provide early confirmation of the diagnosis. ^, Causative organisms of mucormycosis can be visualized on histopathology via commonly used tissue stains. Hyphae of Mucorales are large with variable width (6 to 25 μm), irregular, and ribbon-like in appearance, contain few or no septations, and demonstrate wide-angle (90-degree) branching. As histology often offers the first clues to pathogen identification, it is critical to recognize these morphologic characteristics of Mucorales and to identify how they differ from other fungi. For example, hyphae in invasive mucormycosis differ from invasive aspergillosis (regularly septate, smaller hyphae). In some cases, damage to tissue or a paucity of organisms precludes differentiation of Mucorales from other molds via conventional histopathology. Therefore additional methods for identification of the organism are necessary. This can include a constellation of diagnostic testing, including immunohistochemistry, conventional culture, and more contemporary molecular methods. Practitioners should also be aware of the possibility of co-infection with other molds.

Owing to the lack of septations, the organisms are prone to shearing during tissue processing, and culture results may be negative even with organisms visualized on histopathology. Mincing of tissues rather than grinding is recommended to improve recovery in culture. Speciation of the Mucorales is difficult using conventional microbiology methods, but can be improved using adjunctive molecular methods. The ESCMID/ECMM and ECIL guidelines for mucormycosis recommend identification to the genus and species level, if possible, primarily for epidemiologic understanding. It is not clear at this time that identification of the genus and species is important to guide clinical management. Standardized methods of microdilution susceptibility testing for the Mucorales are guided by the European Committee on Antimicrobial Susceptibility Testing and Clinical & Laboratory Standards Institute, but no validated susceptibility breakpoints have been established. Methodologies for determining an epidemiologic cutoff value have been developed and used for common species. These cutoffs can provide a guide to the clinician regarding the relative susceptibility of an organism. However, despite the terminology, epidemiologic cutoffs are not correlates of clinical effectiveness.

Adjunctive and emerging diagnostic tests.

Novel methods show potential to supplement conventional diagnostic methods for mucormycosis. Immunohistochemistry on histopathology samples and molecular detection methods, including polymerase chain reaction–based strategies and matrix-assisted laser desorption ionization time-of-flight mass spectrometry have been demonstrated in small clinical cohorts. Few molecular diagnostic tests are currently available commercially, and there is a lack of standardized approaches. To the extent that these tests are available, they may be useful in providing genus- and species-level identification when Mucorales are detected via conventional methods, in differentiating Mucorales from other molds when histopathologic findings are ambiguous, or improving detection of Mucorales from lower-yield clinical samples such as BAL fluid. When molecular detection methods are used, fresh clinical samples are preferred over formalin-fixed paraffin-embedded samples.

Some of the most promising strategies are those that may establish the diagnosis of mucormycosis without invasive diagnostic sampling. Such strategies include detection of circulating Mucorales DNA in the blood via polymerase chain reaction, detection of Mucorales-specific host immune responses, and detection of a characteristic metabolite signature in exhaled breath. Unbiased pathogen detection via circulating cell-free nucleic acids has also shown potential to detect IMD including mucormycosis. Such methods are promising and may change the future diagnostic strategy for mucormycosis and other IMDs. However, before they are comprehensively validated against conventional diagnostic methods, they should not be considered a replacement for diagnostic biopsy in patients with suspected mucormycosis.

Primary antifungal therapy