Mucormycosis: causes, symptoms, diagnosis, and treatment

Mucormycosis, also known as zygomycosis, phycomycosis, or hyphomycosis, is a rare but fatal inflammatory disease caused by certain fungi, which can invade the nasal cavity, nasal sinus, orbits, brain, lungs, digestive tract, and skin, and can also cause disseminated infection, with acute onset, with rapid progress, with extremely high mortality of more than 50%. Only few patients present chronic infections, so definitive diagnosis is barely provided before death and is often made in autopsy.


Causes

The pathogenes are mostly Mucorales, which are extensively distributed in nature, and are common saprophytes of soil, bread, and fruits. The common features are zygospores generated in sexual reproduction and sporangia and sporangiospores generated in asexual reproduction. Wide, non-septate or rarely septate hyphae, and thin walls are present. The pathogens invade mostly blood vessels, resulting in embolism and tissue necrosis. Some members in Mucor, Rhizopus, Absidia, Rhizomucor, Mortierella, Syncephalastrum, Cunninghamella, and Saksenaea can cause infections in human or animal. Although the pathogens are different, the clinical symptoms and histopathology are similar. Rhizopus arrhizus is the most common pathogen of human infection.

These fungi are conditional pathogens. Most patients have diabetic acidosis, malnutrition, severe burns, trauma, surgery, leukemia, lymphoma, AIDS, or other severe wasting diseases, or are using immunosuppressants, cytotoxic drugs, or glucocorticoids. Iatrogenic factors include injections, intravenous transfusion, hemodialysis, and contaminated dressings. Due to decreased immune function, the body loses its protective barrier, and pathogens can invade the human body through the respiratory tract, gastrointestinal tract, and skin and mucous membrane wounds, causing infection.


Signs and Symptoms

Rhinocerebral mucormycosis

Most patients are with diabetic acidosis. Infection often occurs initially in the upper nasal turbinates or nasal sinuses, as well as the palate and pharynx, and can cause severe cellulitis. The nasal discharges are sticky, black, bloody. Black necrotic areas can be found in local examination. There are sinusitis and scabs on the hard palate. Blurred nasal sinuses and air fluid levels can be seen in X-ray examination, and sharply demarcated, indurated masses on bilateral nose could be palpable occasionally.

The initial symptoms are mostly unilateral headache, pain and congestion in the nose or nasal sinuses, and serous or black nasal discharge, often with fever.

Severe orbital cellulitis indicates that the pathogens have invaded the eye and central nervous system, and 5th and 7th cranial nerve palsies often occur, with poor prognosis. Ocular symptoms include orbital pain, blepharoptosis, local palsies, exophthalmos and restricted movement, pupil fixation, blindness, palsy of the first and second branches of the trigeminal nerve, and palsy of the ipsilateral facial nerve. As the disease progresses, pathogens invade large cerebral blood vessels, causing embolism and necrosis. Coma is preceded by lethargy, and patients die in as short as 2 days, as long as 2 months, generally 7 - 10 days.

Other symptoms include postocular pain, increased intracranial pressure, and increased white blood cell count. The infection can spread to the lungs or the whole body. The fatality rate is as high as 80% - 90%, and can decline to 50% after administration of amphotericin B.

Very few patients present with chronic nasal mucormycosis, and there are granulations containing hyphae only in the nose. The patients are generally healthy.

A small number of patients have localized granuloma in the brain, without symptoms and signs of nasal infection.

The pathogens are predominantly Rhizopus oryzae and Rhizopus arrhizus.

The outcome and prognosis of rhinocerebral mucormycosis in diabetic patients are often closely related to control of acidosis. If acidosis can be under control, the symptoms will be reduced or even absent until next acidosis occurs.

Pulmonary mucormycosis

Pulmonary mucormycosis can be primary or secondary. Primary infections are more common in patients with lymphoma, leukemia, or diabetes, and is caused by inhalation of fungal spores, while secondary infections are mostly caused by the exposure to secretions of rhinocerebral mucormycosis.

Pulmonary mucormycosis is mainly manifested by progressive non-characteristic bronchitis and pneumonia. In severe cases, pathogens invade blood vessels, causing embolism and necrosis. Fatal hemoptysis resulting from the involvement of arteries or large cavities in the lungs are present in some patients. Most patients die within 3 - 30 days after onset.

Persistent high fever, cough, chest pain, and hemoptysis are present. Antibacterials are ineffective.

A small number of patients present with chronic localized pulmonary mucormycosis. If treated promptly, the prognosis is good. Occasionally, fungus balls may occur in the cavity.

Gastrointestinal mucormycosis

Gastrointestinal mucormycosis is more common in malnourished children caused by typhoid fever, amoebic dysentery, or other diseases. Lesions can involve the esophagus, stomach, ileum, rectum, liver, gallbladder, spleen, and pancreas, and even peritonitis may occur. Symptoms vary depending on the location and degree of involvement, and are usually non-specific abdominal pain, gastric ulcers, stomachache, diarrhea, hematochezia, and coffee ground vomitus. Most patients die of intestinal perforation, pyosepticemia, or hemorrhagic shock within 70 days after onset.

Cutaneous mucormycosis

Most secondary infections are derived from the dissemination of mucormycosis in the lungs or other areas, and patients are mostly with leukemia. The skin lesions are initially painful nodules, gradually expanding. The pale edges are surrounded by narrow red rings, with a diameter of up to several centimeters. Subsequently, central ulcers, eschars, and necrosis occur, and scars may occur. Primary cutaneous and subcutaneous infections are often caused by trauma, surgery, or contaminated dressings. The skin lesions have various morphologies, including papules, plaques, pustules, ulcers, deep abscesses, and ulcerative necrosis. Primary cutaneous mucormycosis generally does not cause hematogenous dissemination, and the prognosis is generally good. The pathogens are predominantly Rhizopus rhizopodiformis and Mucor ramosissimus.

Figure 1 cutaneous mucormycosis

Figure 2 cutaneous mucormycosis

Disseminated mucormycosis

Disseminated mucormycosis is more common in patients with neutrophilopenia and pulmonary mucormycosis. The most common site of dissemination is the brain, followed by heart, spleen, skin, and other organs.


Histopathology

There are usually suppurative inflammatory reaction with abscess formation and suppurative necrosis. The necrotic tissue contains wide hyphae surrounded by a peripheral narrow zone composed of polymorphonuclear giant cells. Massive necrosis and extensive infiltration of polymorphonuclear leukocytes can be seen in severely infected tissues. Chronic infections are rare, and are manifested by simple granuloma reaction or mixed pyogenic and granulomatous inflammatory response. Angionecrosis and mycotic embolism can be seen in the infected tissue, which cause tissue infarction or blood and lymphatic vessel diffusion, often involving large blood vessels. The inflammation in ischemic necrosis areas is mild.

The hyphae in the tissue are wide, with a diameter of 3 - 25μm, averagely 12μm, with a length of up to 200μm, mostly hollow. The mycelia are unbranched or irregularly branched, with perpendicular branches. The hyphae are thin-walled and occasionally septate. The two sides of mycelia are not parallel, sometimes twisted, folded, or oddly shaped, occasionally with local vesicular enlargement. Sporangia and sporangiophores are occasionally seen in some air-contact areas such as the nasal sinuses. HE stain is appropriate, and no other special stains are required.


Diagnosis

If acute and rapidly progressing sinusitis, orbital cellulitis, bronchitis, or bronchopneumonia occur in patients with diabetes, the disease should be considered. Definitive diagnosis is based on the hyphae found in microscopy or histopathology.

Mucor has aerial hyphae widely found in nature, so fungi isolated from non-sterile site specimens such as sputum and nasal secretions may not have clinical significance.


Treatment

Effective antifungal treatment should be preceded by control of diabetes, and the correction of immunosuppressive state or withdrawal of deferoxamine should be considered if possible.

Amphotericin B lipid preparations 7.5 - 10 mg/kg intravenously once daily is recommended as the initial treatment. Recent evidences suggest that posaconazole may be effective, especially as an antifungal treatment option in the consolidation period, but the efficacy of posaconazole as an initial treatment regimen has not been studied.

Surgical excision of necrotic tissue is critical to the treatment of this disease.