Mucormycosis

Mucormycosis (also called zygomycosis) is a serious, relatively uncommon invasive fungal infection and one of the most aggressive and lethal invasive mycoses. Physicians caring for patients with diabetes mellitus, immunocompromise (including that following organ transplantation), or iron overload syndromes (particularly those associated with hemodialysis) should be acutely aware of the enhanced susceptibility of these individuals to infection with the Mucorales.Timely diagnosis is critical to survival and minimization of morbidity. Institution of aggressive surgical and medical therapy is critical in maximizing the likelihood of a good outcome. Delay in considering the diagnosis and instituting appropriate therapeutic measures results in increasingly severe disfigurement at best and in death at worst. 

ETIOLOGY 

Fungi from the order Mucorales are the etiologic agents of mucormycosis. Despite the name of this infection, Mucor is not the most common genus recovered from patients. Rather, Rhizopus and Rhizomucor are the genera usually cultured from tissue samples. Other, less common fungi, including Absidia, Cunninghamella, Apophysomyces, and Saksenaea, are increasingly being isolated and, for the most part, cause similar clinical syndromes. Thus, there is no specific clinical feature that permits identification of the precise fungus involved. Submission of appropriate biopsy material to the microbiology laboratory is mandatory to ensure a pathogen’s identification. 

PATHOGENESIS 

Mucorales are found commonly in the environment, and spores of these usually nonpathogenic fungi are likely to be inhaled daily. In the normal human lung, spores are inhibited from germinating into hyphae by alveolar macrophages. However, in diabetic patients, especially those with elevated blood sugar levels and acidemia, the spores germinate, hyphae develop (Fig. 109-1), and the fungi begin an inexorable march throughout the lung tissue, invading blood vessels and surrounding tissues. As blood vessels become involved, thrombosis occurs, tissue necrosis results, and the fungi continue to grow in this devitalized tissue. The use of deferoxamine to treat iron overload is a risk factor for mucormycosis; the siderophore supplies the fungi with iron that enhances their growth.  Spores settle in the upper airways, lower airways, or gastrointestinal tract and can spread beyond the initial site of infection, causing disseminated mucormycosis. Increasingly, patients are presenting with extensive cutaneous involvement after direct implantation of spores into the skin as a result of trauma (e.g., that sustained in a motor vehicle accident). The pathology in all these sites is the same, with blood vessel invasion and tissue necrosis as hallmarks and specific organ dysfunction depending on the location of the infection. 

CLINICAL MANIFESTATIONS 

The manifestations of mucormycosis depend on the site of infection. Patients with rhinocerebral mucormycosis may present with symptoms typical of sinusitis. However, progression of symptoms over several days indicates a more serious process than the more common bacterial or viral sinusitis. As the infection spreads, hypesthesia or numbness of the face overlying the infection may develop. Concomitant symptoms include headache, bloody nasal discharge, and changes in mental status. The black eschar of the palate is widely described as a hallmark of rhinocerebral mucormycosis, but the astute clinician will recognize earlier manifestations of this end-stage lesion reflecting invasion of the palate. These subtler lesions, which may consist of discolored, often hyperemic areas on the palate, will, if untreated, progress rapidly to the commonly recognized black eschar, which indicates angioinvasion and tissue necrosis. Involvement of the orbit (Fig. 109-2) compromises proper ocular-muscle function and normal movement of the eye within the skull, resulting in double vision. If the blood supply to the eye is affected by invasion of the retinal artery, blindness develops, often quite rapidly. Proptosis and ptosis are late findings reflecting a mass lesion within the orbit and cranial nerve involvement, respectively. Progression of the infection into the brain results in the formation of brain abscesses and phlegmon; symptoms and signs depend on the location of these lesions. Cavernous sinus thrombosis is an ominous sign. CT and MRI reveal sinus opacification and destruction of contiguous bone, and brain involvement can be readily appreciated. Pulmonary mucormycosis presents as severe, progressive, tissue-destructive pneumonia. Neutropenia is a common predisposing factor.A high fever and a critical clinical condition are typical. Cavitation of involved lung develops rapidly, and hematogenous spread beyond the lungs to the brain and other organs may occur. Gastrointestinal mucormycosis occurs primarily in those patients with protein-calorie malnutrition and usually presents as a perforated viscus. Premortem diagnosis is rare, and most patients with this form of mucormycosis do not survive. Cutaneous mucormycosis is more common than disease at other sites and develops after traumatic injuries in which wounds are contaminated with dirt. Areas of tissue necrosis enlarge rapidly, involving all layers of the skin and underlying structures. 

DIAGNOSIS 

Laboratory Features There are no pathognomonic hematologic changes.The abnormalities that are found reflect underlying predisposing conditions (e.g., diabetic ketoacidosis) and general indications of infection, such as elevated white blood cell counts and acute-phase reactant levels. Blood cultures are virtually always negative. Microscopic examination and culture of biopsy samples from the involved area are critical in making an accurate diagnosis. As much tissue as possible should be submitted to the microbiology and histopathology laboratories. Swabs are insufficient. These fungi grow rapidly and are usually visible on culture plates within a day or two.Their identification is based on traditional morphologic features. Fixed tissue samples are treated with special stains for fungi; for example, Gomori methenamine silver stains the fungi black against a green background, and periodic acid–Schiff stains the hyphae red. Mucorales appear as broad (diameter, 6–50 m), usually nonseptate hyphae with branches at right angles; the organisms are often described as ribbon-like. Hyphae cut and viewed on end can deceptively appear yeast-like.The microscopic appearance of the Mucorales is sufficiently different from that of Aspergillus, Fusarium, and other pathogenic molds (which characteristically appear as narrow, septate hyphae with narrow-angle branching) that a pathologist can readily make a preliminary diagnosis of mucormycosis. Identification of the specific organism requires culture. In the laboratory, each species of Mucorales exhibits characteristic morphologic features that permit specific identification. Molecular methods of speciation are still used only as research tools. Differential Diagnosis Other fungal infections, including aspergillosis, fusariosis, and scedosporiosis, must be ruled out by culture and histopathologic analysis. Microscopic examination easily distinguishes the etiologic agents of these infections from the Mucorales. Aggressive pyogenic bacterial infections—e.g., those caused by Pseudomonas, Aeromonas, or Vibrio species; Staphylococcus aureus; and a variety of anaerobes—occasionally produce similar clinical presentations but can be ruled out by Gram’s staining, culture, and microscopic analysis of tissue samples.  Treatment: 

MUCORMYCOSIS 

Three factors are key to a successful outcome of therapy for mucormycosis: (1) reversal of the underlying predisposition; (2) aggressive surgical debridement; and (3) aggressive antifungal therapy, with early initiation and high drug doses. Failure to undertake all three of these interventions simultaneously has a significant and negative impact on outcome. Reversal of underlying disease is relatively easy in patients with diabetic ketoacidosis but is more difficult in patients who require continued immunosuppression for control of an underlying disease or after organ transplantation. In all cases, minimization of immunosuppressive medications enhances overall control of the fungal infection. Aggressive surgical debridement requires the removal of all dead tissue and of tissue that appears to be so severely compromised that its continued viability is in question. Extensive reconstructive surgery may be required once the infection has been cured. Traditionally, high-dose conventional amphotericin B has been used for the treatment of mucormycosis, but doses have been limited to 1.5 mg/kg per day because of the nearly universal development of nephrotoxicity. Use of lipid formulations at doses of 15–20 mg/kg per day (AmBisome) or 15 mg/kg per day (Abelcet) maximizes the amount of amphotericin B delivered to the tissues as well as the speed of its delivery. At these doses, nephrotoxicity occurs in 50% of patients. 

Posaconazole, an experimental triazole antifungal agent, has been shown to be active against mucormycosis in mouse models of infection and in patients who cannot tolerate or do not respond to other antifungal drugs. The precise clinical role for posaconazole in the treatment of mucormycosis is not clear, but this drug may prove to be a valuable alternative to amphotericin B in selected cases. Given the relative rarity of mucormycosis, it is not likely that a randomized study will rigorously compare the roles of the various antifungal agents. The optimal duration of therapy for mucormycosis is not known precisely. If possible, antifungal administration should be continued for at least 3 months after (1) all clinical abnormalities resolve or stabilize, leaving no clinical evidence of infection at the involved site(s); and (2) scans, x-rays, and laboratory studies yield normal or stable results. Careful follow-up should continue for at least 1 year to confirm that there is no evidence of recurrent infection. With this approach, recurrences should be rare.