Definition, Etiology, PathogenesisTop
Mucormycosis is an infiltrating fungal infection leading to destruction of tissues.
1. Etiologic agent: Fungi of the genus Mucorales, typically Rhizopus spp (the most common cause of mucormycosis), Lichtheimia spp (former Absidia and Mycocladus), Mucor spp, and less frequently Rhizomucor spp, Saksenaea spp, Cunninghamella spp, and Apophysomyces spp.
2. Pathogenesis: In tissues the fungus forms hyphae that grow into an extensive mycelium infiltrating the adjacent tissues and leading to their destruction. Infiltration of blood vessels, infarcts, necrosis, and thrombosis are observed. The disease typically progresses rapidly. Neutrophils play a key role in natural defense processes.
3. Reservoir and transmission: The fungi that cause mucormycosis are found in soil and decaying organic matter. The infectious material is spores. Transmission may be via inhalation (pulmonary and rhinoorbitocerebral mucormycosis), ingestion (gastrointestinal [GI] mucormycosis), and skin (injuries, cuts with contaminated objects; cutaneous mucormycosis).
4. Risk factors: Uncontrolled diabetes (particularly patients with ketoacidosis), neoplastic diseases (particularly myeloproliferative neoplasms), neutropenia, immunosuppression (glucocorticoids, tumor necrosis factor [TNF]-alpha inhibitors), hematopoietic stem cell transplant, graft-versus-host disease (GVHD), concomitant opportunistic infections (particularly cytomegalovirus [CMV] infections), injuries (cutaneous mucormycosis), burns, IV illicit drug use, cachexia (favors intestinal mucormycosis), elevated iron levels, treatment with deferoxamine (risk of angioinvasive mucormycosis), past coronavirus disease 2019 (COVID-19).
Risk factors for GI mucormycosis include consumption of fermented porridge and alcoholic beverages made from corn, using herbs or homeopathic agents contaminated with spores, using contaminated dental instruments (iatrogenic infection).
5. Incubation and infectious period: The incubation period is not known; the pathogen demonstrates low infectivity and high virulence once the host defense mechanism is breached. No human-to-human transmission has been reported. Hospital-acquired infection is possible (through equipment contaminated with spores).
Different species of fungi that cause mucormycosis are dominant in different parts of the world. In Europe Rhizopus spp causes 34% of infections, Mucor spp, 19%, and Lichtheimia spp, 19% as well. The dominant species in India is Rhizopus, but infections with Apophysomyces elegans, Apophysomyces variabilis, Mucor irregularis, and Thamnostylum lucknowense have also been described. The number of patients with mucormycosis in resource-rich countries is growing. This is due to advances in medicine, which result in expansion of populations with risk factors. A rapid growth in the incidence of mucormycosis as a fungal superinfection has been reported in India during the COVID-19 pandemic.
The risk factors affect the prevalence of the specific types of mucormycosis; pulmonary disease is more common in individuals with agranulocytopenia and GVHD, while rhinoorbitocerebral mucormycosis, in patients with diabetes; immunocompetent individuals usually have cutaneous disease (infection is acquired by direct inoculation through trauma, eg, during traffic accidents, explosions, burns, surgical procedures); those using IV psychoactive substances typically have isolated renal mucormycosis.
CLINICAL FEATURES AND NATURAL HISTORYTop
1. Rhinoorbitocerebral mucormycosis: The majority of cases of rhinoorbitocerebral mucormycosis occur in patients with diabetes. Infection is via inhalation of spores into paranasal sinuses. The expanding mycelium rapidly infiltrates the surrounding tissues causing their destruction and progresses to the palate, sphenoid sinus, cavernous sinus, and orbits. Infection spreads to the nervous system by continuity. The mycelium may spread by blood, sometimes with aneurysm formation. Early manifestations resemble sinusitis with periorbital swelling, eye pain, facial pain, or all of these. Symptoms of cranial nerve palsy, ptosis, proptosis, acute impairment of ocular movement, ophthalmoplegia, or loss of vision may develop. A black eschar appears on the skin. Fever develops in ~50% of cases. Bone erosion is usually visible on radiographs in late disease; at earlier stages, soft tissue necrosis is observed.
2. Pulmonary mucormycosis: The disease is more common in individuals with neutropenia secondary to chemotherapy and in those with GVHD after hematopoietic stem cell transplant. The manifestations are nonspecific and initially resemble aspergillosis. Patients have chronic fever that does not subside following the use of broad-spectrum antibiotics. Chronic nonproductive cough is frequently reported while hemoptysis, chest pain, and dyspnea are rare. The trachea and bronchi may occasionally be involved, particularly in persons with diabetes. Endobronchial mucormycosis leads to airway obstruction, atelectasis, and occasionally to infiltration of vessels of the hilum, mediastinum, pericardium, and chest wall.
3. GI mucormycosis: Intravital or supravital diagnosis is rarely made. Any section of the GI tract may be involved, with stomach being the most common site. The mycelium infiltrates the GI wall and vessels and leads to perforation, peritonitis, sepsis, GI hemorrhage; infiltrates may also be observed in the liver, spleen, and pancreas.
4. Cutaneous mucormycosis: Infection is via direct spore inoculation into the skin; blood-borne infections are rare. The following types of the disease are distinguished: cutaneous/subcutaneous infection; deep infiltration (with muscle, tendon, and bone involvement); and disseminated disease (with other organs affected). Indurated necrotic lesions with an eschar surrounded by erythema are typical. Other nonspecific lesions may also develop such as macules, ulcerations, or plaques. Cutaneous mucormycosis may progress slowly or fulminantly.
5. Disseminated mucormycosis: Develops from localized infection as a result of hematogenous dissemination of the mycelium to other organs (typically to lungs).
1. Identification of the etiologic agent:
1) Direct microscopic examination of clinical specimens allows for initial diagnosis of mucormycosis but not for species identification.
2) Culture allows for identification of fungal genus and species, and for assessment of drug susceptibility. Biopsy with culture or, for pulmonary mucormycosis, bronchial wash culture are performed. Blood and cerebrospinal fluid (CSF) cultures are usually negative. Testing should be performed in a specialized mycologic laboratory, taking into account the environmental requirements of individual species; tissue homogenization may destroy the mycelium, thus making the culture ineffective.
3) Histologic studies: If mucormycosis is suspected in individuals at high risk of the disease, biopsy of affected tissues is recommended in all cases. Histologic studies visualize the hyphae, but culture is needed to differentiate mucormycosis from other systemic mycoses (microscopic image may resemble Aspergillus spp). Immunohistochemical techniques or polymerase chain reaction (PCR) may be helpful due to high specificity.
4) There are no standardized molecular tests.
2. Other findings:
1) Laboratory tests: Leukocytosis is typically present in patients with functioning immune system.
2) Imaging studies reveal infiltration and destruction of tissues, and are also used for assessment of treatment efficacy (eg, weekly in the initial phase).
a) Rhinoorbitocerebral mucormycosis: Contrast-enhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) of the paranasal sinuses (needed prior to surgery) visualize the extension of tissue damage. Contrast-enhanced MRI is useful in the assessment of intracranial lesions, including the cavernous sinus and internal carotid artery thrombosis, and in visualization of mycelium expansion along the nerves.
b) Pulmonary mucormycosis: The lesions are usually nonspecific and resemble those in aspergillosis. Typical findings include infiltrates, consolidations, nodules, cavitary lesions, atelectasis, exudates, thickened posterior tracheal wall, and enlarged lymph nodes in the hila and mediastinum. A >10-fold enlargement of lymph nodes and pleural effusion are indicative of mucormycosis. Radiologic features may be, however, unremarkable.
Sinusitis, periorbital infection, cavernous sinus thrombosis, aspergillosis, Pseudallescheria boydii infection, orbital tumor, nocardiosis, granulomatosis with polyangiitis (formerly Wegener granulomatosis), pulmonary embolism, anthrax.
In immunocompromised individuals with suspected mucormycosis, treatment should be started immediately, without waiting until the end of diagnostic workup.
Treatment of the Underlying Condition
1. Antifungal treatment:
1) Initial treatment:
a) Treatment of choice: IV liposomal amphotericin B (LAmB), dosed at 5 to 10 mg/kg daily (10 mg/kg if brain tissue is involved). Gradual dose uptitration is not recommended; the full dose should be used starting day 1 of treatment.
b) Alternative treatment (options): IV posaconazole 300 mg, 2 doses on day 1, then once daily; or IV isavuconazole 200 mg (equivalent to isavuconazonium sulfate 372 mg [prodrug]) every 8 hours for 2 days (a total of 6 doses), followed by 200 mg once daily.
2) Maintenance treatment:
a) Stabilized disease, partial remission: Continue the treatment or switch to oral isavuconazole or posaconazole (for posaconazole use delayed-release tablets).
b) Progressing disease: Oral or IV isavuconazole 200 mg (equivalent to isavuconazonium sulfate 372 mg [prodrug]) every 8 hours for 2 days (a total of 6 doses); then 200 mg once daily; or IV or oral posaconazole (delayed-release tablets), 300 mg bid on day 1, then 300 mg once daily; or IV LAmB 10 mg/kg daily.
If LAmB-related nephrotoxicity is observed, use isavuconazole or posaconazole.
The duration of treatment is to be specified on a case-by-case basis. The European Confederation of Medical Mycology (ECMM) recommends continuation of treatment until the immune defect resolves and complete remission is seen on imaging. In some cases treatment may last several years.
In immunosuppressed individuals with previous diagnosis of mucormycosis, resection of lesions and continuation or resumption of the most recently used drug effective for the patient is recommended. In individuals with neutropenia or GVHD, the ECMM recommends primary prophylaxis with posaconazole (delayed-release tablets).
2. Surgical treatment: Early surgical treatment is recommended where possible. If necessary, resection of infiltrated tissues should be repeated.
Rhinoorbitocerebral mucormycosis manifesting with permanent tissue damage with erosions, eye loss, brain damage.
The disease progresses rapidly, and mortality depends on the type; for rhinoorbitocerebral mucormycosis it is between 50% and 70%; for pulmonary disease, ~75%; for disseminated disease, 100%; and for cutaneous, 15%. The risk of death also depends on the cause of impaired immunity.
1. Immunoprophylaxis: None available.
2. Chemoprophylaxis: In individuals with neutropenia or GVHD, the ECMM recommends primary prophylaxis with posaconazole (delayed-release tablets).
1. Avoiding exposure to decaying organic matter (plant- and animal-derived) by individuals from the risk group.
2. Patient isolation is not required.
3. Personal protective equipment (PPE): Standard.