Mucormycosis

Etiology

Mucormycosis is an infectious disease caused by a fungus of the class 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). These are common environmental organisms that are not harmful to immunocompetent humans. In patients with overt immunocompromise (i.e., transplant patients, HIV, patients of chronic steroids or disease-modifying anti-rheumatic medications, leukemia or other cancer patients), they can present with rapidly progressive necrotizing infection. Similarly, uncontrolled diabetics (particularly those with a history of diabetic ketoacidosis) are also at risk.[1][2][3]

Epidemiology

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, though various Aspergillus species are also commonly encountered. Mucormycosis has increased its frequency because of the increased prevalence of immunosuppression states in the general population owing to improved lifespan in cancer and transplant patients, as well as expanding indications for immunosuppressive medications for various autoimmune diseases.

The primary route of infection is via air spore inhalation, which deposits in the paranasal sinuses and the lungs. 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.

The most commonly encountered clinical form is rhinocerebral mucormycosis, and the resultant mortality, even with pharmacological and/or surgical treatment, is high unless the immune system status can be restored.[1][4]

Pathophysiology

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. This is seen clinically in patients with leukemia and bone marrow transplants, who are at the highest risk.

Rhizopus arrhizus studies 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 host tissues and then invade blood vessels. This extensive angioinvasion results in vessel thrombosis and tissue necrosis. Patients with diabetes usually present with clinically uncontrolled diabetes and increased amounts of circulating glucose, 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 and causing extensive areas of ischemic necrosis.

Also, metabolic acidosis prevents chemotaxis of polymorphonuclear leukocytes, causes decreased phagocytic activity, and reduces local inflammatory response in a patient whose immune system is already compromised from one or more additional diseases.[4][5]

Histopathology

Histological evaluation of mucormycosis is the mainstay of diagnosis. 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. Even Aspergillus can be potentially pathologic in these patients. Cultures should be sent from tissue biopsy specimens for completeness, but the slow-growing nature of such fungi in culture will often preclude these tests from being clinically useful, as the patient may expire from the infection long before the cultures have yielded answers.

As such, histopathology allows the differentiation of mucormycosis from aspergillosis. Biopsy techniques will vary depending on the anatomic location. The paranasal sinuses are the most common location, and biopsy can be performed directly or endoscopically. Other locations (lungs, gastrointestinal tract, etc.) may require more invasive endoscopic procedures to obtain tissue for histology, though interventional radiologic techniques can also be helpful. Notably, the absence of hyphae should not dissuade one from the diagnosis when the presence of risk factors and the clinical findings suggest this infection, and treatment may be guided by clinical parameters even if only yeast forms are observed on histology.[4][6]

History and Physical

Mucormycosis can invade different body systems. Sites of infection include the lung, central nervous system, paranasal sinuses, gastrointestinal system, and 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 is initiated with the inhalation of spores into the paranasal sinuses and the invasion of blood vessels in the tissue. The infection starts with nasal congestion or discharge, though it may progress to facial numbness, blurry vision, nasal discharge, nasofrontal headache, ocular pain, fever, diplopia, and chemosis. Intranasal lesions characteristically have painless ulcerations with exudate and necrotic tissue and usually progress rapidly over days. In an immunocompromised patient with prolonged nasal symptoms, one should maintain a low threshold to obtain a biopsy to rule out mucormycosis (often termed "invasive fungal sinusitis - IFS).

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 pulmonary embolism. The infection can spread to contiguous tissues, such as the mediastinum and heart. However, it may also lead to cavitary lesions that can mimic tuberculosis or more benign allergic fungal disease. 

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, though the use of contaminated herbal medicines has 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. Gastrointestinal symptoms are rare in all but the most severely immunocompromised (leukemia patients, intestinal transplant patients, etc.) owing to a large amount of immune tissue in the GI tract.

The disseminated form of mucormycosis may originate from any primary sites of infection, and manifestations are nonspecific, which makes diagnosis even harder, but a metastatic skin lesion is undoubtedly a sign to suspect disseminated mucormycosis and portends a dismal prognosis.[4][5][7][8][9]

Evaluation

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 intervention in the suspicion of rhinocerebral mucormycosis is with the endoscopic evaluation and biopsy of the sinuses to examine for tissue necrosis and to obtain examples of tissue. The presence of characteristic hyphae provides a presumptive diagnosis. The area of highest yield and greatest accuracy is to biopsy the middle turbinate. A computed tomography (CT) scan can help evaluate contiguous structures such as the eyes and brain. Findings in the 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.[7][10]

Treatment / Management

The standard management of mucormycosis requires early diagnosis, a reversal of risk factors and underlying illness, surgical debridement, and prompt administration of intravenous antifungals - usually amphotericin B. This entails the prompt management of hyperglycemia, acidosis, and cessation of immunosuppressive agents when possible.

Amphotericin B is considered 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. This may involve radical facial resections, partial pneumonectomy, colectomy, etc., in accordance with the site of disease. Similar to necrotizing fasciitis, this requires very aggressive surgical management and often carries dramatic morbidity. Unless the immune status can be restored, the outcomes are unfortunately very poor, even with the most aggressive therapies and drastic surgical intervention.

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. 

Other adjuncts include hyperbaric oxygen. The increased oxygen pressure improves the ability of neutrophils to kill the organism and facilitates wound healing.[10][6]

Differential Diagnosis

In the case of mucormycosis in its rhinocerebral form, consider different pathologies, such as orbital cellulitis and cavernous sinus thrombosis.

When considering the diagnosis of pulmonary mucormycosis, one should think about aspergillosis, nocardiosis, and granulomatosis with polyangiitis (Wegener granulomatosis).[11]

Prognosis

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.

The severity and poor prognostic indicators include disseminated infection, renal injury, central nervous system disease, and inadequate response to medical treatment. The most important prognostic factor is the ability to restore a normal immune status. If this is not possible, the prognosis is uniformly dismal. If immunocompetence can be restored, even temporarily, then prognosis does improve.[11]

Complications

The 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 include cavernous sinus thrombosis, disseminated infection, periorbital destruction, palatine ulcers, osteomyelitis, and death.

Complications due to treatment are nephrotoxicity, hypokalemia, and prolonged hospitalization (specifically with the use of deoxycholate amphotericin B).