Mucormycosis is an opportunistic fungal infection of the zygomycete family that can cause various types of infections. In most cases, there exist underlying conditions that predispose the hosts to the infection. There are several clinical forms of infection: pulmonary, gastrointestinal, cutaneous, encephalic, and rhinocerebral. Mucormycosis is characterized by tissue necrosis due to an invasion of blood vessels and subsequent thrombosis, which usually follows a rapid progression. The key to treatment is early and aggressive surgical debridement, along with high doses of intravenous antifungal therapy.
Mucormycosis is an infectious disease caused by a fungus of the class of Zygomycetes and the order of Mucorales.
The species most frequently isolated from patients are: Apophysomyces (A. variabilis), Cunninghamella (C. bertholletiae), Lichtheimia [Absidia] (L. corymbifera L. raosa), Mucor (M. circinelloides), Rhizopus (R. arrhizus (oryzae) R. microsporus), Rhizomucor (R. pusillus), and Saksenaea (S. vasiformis).
Mucorales are thermotolerant fungi found in soil and decaying matter and rarely cause disease because of low virulence. Rhizopus is considered the most frequent fungal infection in immunocompromised populations. Mucormycosis has increased its frequency because of the increased prevalence of immunosuppression states in the general population.
The primary route of infection is via air spore inhalation, which deposits in the paranasal sinuses and the lung. Other routes less frequently encountered result from ingestion or direct skin inoculation.
Risk factors include diabetes mellitus, malnutrition, malignancies (lymphomas and leukemias), renal failure, organ transplant, burns, immunosuppressive therapy, cirrhosis, and AIDS. Patients with diabetic ketoacidosis and patients on dialysis who receive treatment with iron chelator deferoxamine are also more susceptible to mucormycosis.
Mucorales are present in soil and decaying matter, in immunocompetent people, the spores of Mucorales that reach the respiratory tract adhere to the nasal mucus and are eliminated either by swallowing or sneezing, if there is any wound in the mucous membranes, the polymorphonuclear neutrophils phagocytose and destroy the fungal structures. Neutrophils are the host defense against these infections; therefore, individuals with neutropenia or neutrophil dysfunction are at the highest risk.
Rhizopus arrhizus have demonstrated that the ketone bodies present in these patients are metabolized by a ketone reductase, which allows them to survive in conditions with an acid medium thus the fungi become hyphal forms in tissues then invade blood vessels, this extensive angioinvasion results in vessel thrombosis and tissue necrosis. Diabetes patients usually present with a large amount of glucose in tissues and exudates, providing excellent conditions for the rapid development of filamentous structures that first bind to blood vessels and then penetrate them completely clogging them in a few days, causing extensive areas of necrosis.
The microscopic examination and culture of samples of the affected tissue are the main pillars in the histological evaluation of mucormycosis in its different forms. Diagnosis occurs through observing non-septate or minimally septated broad, ribbon-like hyphae (10 to 20 micrometers) invading blood vessels. The microscopic examination should evaluate morphology, width, branching angle, and septation.
It is challenging to get the proliferation of these fungi from the infected tissues. Once achieved, proliferation is rapid and diffuse in most culture media at room temperature. The biopsy is obtainable by imaging-guided biopsy, transbronchial biopsy, endoscopy with biopsy of the sinuses or gastrointestinal tissue, and skin biopsy. As such, histopathology allows the differentiation of mucormycosis from aspergillosis. Notably, the absence of hyphae should not dissuade from the diagnosis when the presence of risk factors and the clinical findings suggest this infection.
Mucormycosis can invade different body systems. Sites of infection include the lung, central nervous system, paranasal sinuses, gastrointestinal system, and the skin. Its clinical manifestations are varied but characteristically demonstrate rapid progression. The clinical manifestations largely depend on the route of entry of the fungus and the predisposing disease.
Rhinocerebral mucormycosis initiated with inhalation of spores into the paranasal sinuses and the invasion of blood vessels in the tissue. The infection stars with fever, nasal congestion, facial numbness, blurry vision, nasal discharges, nasofrontal headache, ocular pain, diplopia, and chemosis. Dermatological lesions in the nostrils characteristically have ulcerations and necrotic tissue, usually progress rapidly over days.
Pulmonary mucormycosis consists of the development of bilateral pneumonia, which is rapidly progressive and the result of the inhalation of infectious material. The most common clinical features are fever, hemoptysis, dyspnea, and cough. This clinical form is seen more frequently in patients with hematological diseases. This pulmonary condition can present as bronchitis, bronchopneumonia, and even pulmonary embolism. The infection can spread to contiguous tissues, such the mediastinum, and heart.
Cutaneous mucormycosis presents in both primary and secondary disease. In primary disease, the skin infection results from direct inoculation and in secondary form, by dissemination from other locations. The primary form often occurs in patients with burns and traumatic skin wounds, usually appears as a single and indurated area of cellulitis that progresses a necrotic lesion, other forms of manifesting are abscesses, skin swelling, and necrosis.
Gastrointestinal form occurs via the ingestion of contaminated food and the use of contaminated herbal medicines have been linked to gastrointestinal disease development, there may be nausea, vomiting, ulceration, and thrombosis of the gastric, esophageal and intestinal mucosa, manifested by diarrhea, hematemesis, and melena. Perforation and peritonitis can result from necrotic ulcers. Also, the presence of bowel infarctions and hemorrhagic shock lead to poor prognosis.
Disseminated form of mucormycosis may originate from any primary sites of infection, manifestations are nonspecific, which makes diagnosis even harder, but a metastatic skin lesion is undoubtedly a sign to suspect disseminated mucormycosis.
Routine blood work is rarely diagnostic but can find the presence of neutropenia as a correlating risk factor.
Imaging can be valuable in evaluating the extent of the disease. Radiological imaging studies are required to investigate areas with suspected mucormycosis, specifically in the brain, paranasal sinuses, lungs, and abdomen, always guided by the clinic.
The first imaging study in the suspicion of rhinocerebral mucormycosis is with the endoscopic evaluation of the sinuses to look tissue necrosis and to obtain examples of tissue, the presence of characteristic hyphae provides a presumptive diagnosis. A computed tomography scan helps us to evaluate contiguous structures such as the eyes and brain, findings in CT scan included soft tissue edema of cavity mucosa, sinus mucoperiosteal thickening, bone erosions, and orbital invasions.
Patients with immunosuppression and respiratory symptoms should have a CT chest for possible pulmonary mucormycosis. The presentation of the infection does not differ from pneumonia; therefore, the diagnosis is difficult. Chest radiologic findings are pleural effusion, nodules, consolidation, and ground glass infiltrates. Bronchoalveolar lavage can show broad nonseptate hyphae.
If there is a concern for gastrointestinal mucormycosis (abdominal pain, gastrointestinal bleeding), a CT scan to evaluate for colitis is necessary. Once confirmed, colitis should be further investigated by endoscopy with biopsy. The presence of characteristic hyphae in the biopsy provides a presumptive diagnosis.
The standard management of mucormycosis requires early diagnosis, a reversal of risk factors and underlying illness, surgical debridement and prompt administration of intravenous amphotericin B. This entails the prompt management of hyperglycemia, acidosis, and cessation of immunosuppressive agents when possible.
Amphotericin B is considered the first line therapy for mucormycosis. The lipid formulation of amphotericin B is administered in high doses intravenously once a day as initial therapy. The initial starting dose is 5 mg/kg IV daily, with a maximum dose of 10 mg/kg IV. Treatment duration depends upon the patient's clinical picture.
Surgical debridement of infected tissue should be urgently performed to limit the further spread of infection. Aggressive surgical debridement of necrotic tissue should take place immediately.
Posaconazole or isavuconazole has some evidence as second-line therapy in mucormycosis. For salvage treatment posaconazole 200 mg IV four times daily is recommended. The guidelines do not support the combination of amphotericin and posaconazole.
In a case of mucormycosis in its rhinocerebral form, one must consider different pathologies such as orbital cellulitis and cavernous sinus thrombosis.
When we consider the diagnosis of pulmonary mucormycosis, we should think about aspergillosis, nocardiosis, and Wegener's granulomatosis.
The prognosis is dependent upon the timing of therapeutic intervention, as well as the degree of the underlying immunodeficiency of the patient with mortality ranging from 25 to 87% depending on the site of infection.
Severity and poor prognostic indicators include disseminated infection, renal injury, central nervous system disease, and inadequate response to medical treatment.
Complications of mucormycosis subdivide into those that result from the disease itself and those that are caused by the antifungal treatment. Complications associated with the disease are cavernous sinus thrombosis, disseminated infection, periorbital destruction, palatine ulcers, osteomyelitis, and death.
Complications due to treatment are nephrotoxicity, hypokalemia, prolonged hospitalization (specifically with the use of deoxycholate amphotericin B).
The key to the diagnosis is the identification of key risk factors and hallmark symptoms. The "classic" presentation is the immunocompromised patient, with rhinosinusal involvement, demonstrating a very rapid progression of infection, and the presence of tissue necrosis.
Depending on the degree of immunosuppression and predisposing conditions, the progression of the disease can be acute, fulminant, or chronic.
The identification of the exact species that cause mucormycosis is not straightforward due to the difficulty of isolating the fungus in culture media. However, regardless of the causative species and clinical presentation, therapeutic management is the same.
Mucormycosis is a life-threatening fungal infection, with very high mortality. Interdisciplinary management typically consists of infectious disease, otolaryngology, hematology/oncology, endocrinology, microbiology, specialty-trained nursing, and pharmacist assistance of therapeutic drug administration and monitoring, all collaborating across disciplines to achieve optimal patient results. [Level V] However, even with prompt, adequate evaluation and treatment by the interdisciplinary team, the prognosis remains poor.
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