September 21, 2018
Years published: 2018
NORD gratefully acknowledges Dimitrios P. Kontoyiannis, MD, ScD, PhD (Hon), FACP, FIDSA, FECMM, FAAM, Texas 4000 Distinguished Professor for Cancer Research, Deputy Head, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Adj. Professor Baylor College of Medicine, Adj. Professor University of Houston, for assistance in the preparation of this report.
Mucormycosis is a general term for a group of uncommon infections cause by a fungus (fungal infection). Mucormycosis is caused by a group of related molds from the order Mucorales. An “order” is a scientific term for classifying similar organisms. These infections are usually acquired when spores from the molds are breathed in (inhaled) or, less commonly, enter the body through a cut in the skin. Mucormycosis is an aggressive, life-threatening infection that occurs in people whose immune system doesn’t function well (immune-compromised) including people with uncontrolled diabetes mellitus, people who have low levels of neutrophils, a type of white blood cell that helps the body fight off infection and heal itself (neutropenia), or people whose immune system is being suppressed by medications (immunosuppression) as part of their treatment for blood cancer (hematological malignancy), hematopoietic stem cell transplantation, or solid-organ transplant. The infection is not contagious; it cannot be spread from one person to another. Prompt diagnosis and early treatment are critical. Treatment usually consists of antifungal medications and surgery.
Mucormycosis is an invasive fungal infection. These infections were once called zygomycosis, but the organisms that cause the infection, specific types of molds, have been scientifically reclassified and the term mucormycosis is now preferred. Generally, these infections are broken down into five presentations: rhinocerebellar, pulmonary, cutaneous, gastrointestinal, and disseminated.
The most common presentation is a sinus infection (sinusitis) that is accompanied by nasal congestion, nasal discharge, and sinus pain. A fever and headache can also occur. If the infection spreads outside the sinuses, symptoms can include tissue loss (necrosis) of the roof of the mouth (palate), disintegration of thin wall of cartilage and bone (septum) that divides the nostrils (septum), swelling of the area around the nose (perinasal area), and redness (erythema) of the skin overlying the sinus and the eye socket (orbit). Sometimes, there is bluish discoloration of the skin near the sinuses or the eye socket due to a lack of oxygen (cyanosis). Sometimes, blurry vision or double vision can develop. If unrecognized and untreated, significant tissue death (necrosis) can occur and the infection can significantly damage facial structures.
Sometimes, mucormycosis can spread to the brain. This can cause lethargy, seizures, slurred speech, partial paralysis, abnormalities of the nerves of the face and eyes (cranial neuropathies), a brain abscess, altered consciousness, and coma. When the sinuses and brain is involved, this infection can be referred to as rhinocerebral mucormycosis.
When the infection spreads to the eye, there can be swelling due to fluid buildup around the eyes (periorbital edema), bulging or displacement of the eye (proptosis), vision loss, and potentially blindness. Some affected individuals experience paralysis or weakness of the muscles that move the eyes (ophthalmoplegia), making it difficult or painful to move the eyes.
Mucormycosis can affect the lungs (pulmonary mucormycosis), most often when the spores are breathed in and reach the respiratory system. Pulmonary mucormycosis is often a rapidly progressive disease characterized by fever and a cough that does produce any mucous (nonproductive cough). Less often, spitting or coughing up of blood (hemoptysis), chest pain, and difficulty breathing (dyspnea) will occur.
When mucormycosis affects the skin (cutaneous mucormycosis), affected individuals can develop a single, painful, hardened area of the skin and inflammation of the underlying tissue. Nearby skin may become reddened, warm, swollen and painful. Sometimes, open sores (ulcers) and blisters will form and tissue loss (necrosis) can occur with the affected tissue turning black. Affected individuals may have a fever. Cutaneous mucormycosis can develop slowly or be severe and sudden in onset (fulminant).
Sometimes, the gastrointestinal system can be affected. This most likely occurs when spores are breathed into the mouth and swallowed or contaminated food is eaten. Symptoms can include abdominal pain and vomiting of blood (hematemesis). Lesions can develop that cause a hole to form in the stomach or intestines (perforation). Inflammation of the peritoneum (peritonitis), the membrane that lines the wall of the abdomen and covers the organs inside the abdomen, can also develop. Sometimes, severe pain in the bowels can occur because of a lack of blood flow (bowel infarction) and affected individuals can go into shock because of significant blood loss (hemorrhagic shock).
Disseminated mucormycosis is a rare form often seen in individuals who are severely immune-compromised. In this form, the infection spreads to other areas of the body and becomes widespread (disseminated). Other areas that can be affected include the brain, heart, spleen, skin, and other organs.
In rare instances, mucormycosis can affect or spread to affect the kidneys, the inner lining of the chambers of the heart and the heart valves (endocarditis), and the bone (osteomyelitis). Signs and symptoms of disseminated mucormycosis vary greatly depending upon the organ system involved.
Mucormycosis is a fungal infection caused by certain types of mold. These molds are known as mucormycetes. They are found throughout nature (ubiquitous) and can be found in the soil and decaying organic matter like decaying vegetation.
Although they are found commonly throughout nature, these molds normally don’t cause problems. However, in individuals with a weakened or compromised immune system, they can cause severe, even life-threatening, infection. Most people develop this infection by breathing in mold spores. Less often, infection can develop when spores enter the body through a cut or open wound.
There are people who are at a greater risk of developing mucormycosis. These risk groups include people who have low levels of neutrophils (neutropenia), which are white blood cells that help to fight off infection, and are receiving broad-spectrum antibiotics; and individuals who are receiving drugs that suppress the activity of the immune system (immunosuppressive drugs). Neutropenia can be seen in and immunosuppressive drugs can be taken for cancer, especially blood (hematologic) cancers.
Mucormycosis affects people who have recently undergone hematopoietic stem cell transplantation (HSCT). Hematopoietic stem cells are found in the bone marrow and are cells that eventually grow into red blood cells, white blood cells, and platelets. A transplant involves wiping out the existing bone marrow and replacing it with bone marrow from a healthy donor. Affected individuals must take immunosuppressive drugs to help fight off rejection, but this can leave them more susceptible to infection including infection with mucormycosis. People receiving immunosuppressive drugs for other reasons such as receiving an organ transplant can also be at risk of developing this infection.
Some individuals with diabetes may be at risk of developing mucormycosis, especially if their diabetes is poorly-controlled and they develop diabetic ketoacidosis. Ketoacidosis is a complication of poorly-controlled diabetes in which the body produces high levels of blood acids called ketones. Ketoacidosis can cause a variety of symptoms. The exact reasons why people with poorly-controlled diabetes are more susceptible to mucormycosis is not completely understood, although it may be related to these patients have excess iron available in the tissues.
People who have too much iron in the body (iron overload), which occurs because of frequent blood transfusions or in certain blood disorders, are also at risk of developing mucormycosis. Researchers believe that these molds are able to use the excess iron to grow and spread. A medication called deferoxamine, which is used to rid the body of excess iron, can be used by mucormycosis infection to acquire iron from the affected individual. Deferoxamine leads to the growth and spread of infection and the use of this drug is another risk factor for mucormycosis infection.
Other conditions can increase the risk of developing mucormycosis including kidney insufficiency; HIV/AIDS; the use of contaminated medical equipment near or in open wounds; long-term use of corticosteroids, which are very strong anti-inflammatory medications; skin trauma including burns or other injury to the skin; extreme malnutrition; and illegal drug use involving needles. Premature newborns can be at a greater risk to infection including mucormycosis as well.
In rare instances, some people develop mucormycosis, but do not have any identifiable risk factor.
Researchers have determined that mucormycosis infection has a high affinity for the blood vessels. This means that the infection often involves the blood vessels, but researchers do not know exactly why this is so. Infection of the blood vessels can block the flow of blood, depriving tissue of oxygen and causing tissue death (necrosis).
Mucormycosis is a rare fungal infection. The exact number of people who develop this infection in the United States is not known because there is no national surveillance of this infection. One estimate based on a study in the San Francisco area placed the incidence at 1.7 people per every 1,000,000 in the general population. Incidence refers to the number of new diagnoses of a disorder in one year. According to the medical literature, the incidence of mucormycosis is increasing. Mucormycosis has been reported all over the world. This infection can potentially affect individuals of any age, including premature newborns.
Symptoms of the following disorders can be similar to those of mucormycosis. Comparisons may be useful for a differential diagnosis.
Aspergillosis is a fungal infection caused by Aspergillus, a species of mold that is found all over the world. More than 300 different types of Aspergillus have been identified and more are continuing to be identified. Most of these molds are harmless, however, some types can cause a variety of diseases in humans ranging from simple allergic reactions to life-threatening invasive disease. Collectively, this group of diseases is referred to as aspergillosis and is broadly broken down into three categories – allergic, chronic and invasive. Four main clinical types of aspergillosis are usually identified – allergic bronchopulmonary aspergillosis, aspergilloma, invasive aspergillosis, and chronic necrotizing aspergillosis. Aspergillosis rarely develops in healthy individuals; it is much more likely to develop in individuals with asthma, cystic fibrosis, diabetes mellitus, and lung disease or in individuals who have a weakened immune system, who take corticosteroid drugs or who have had a bone marrow or organ transplant. In most cases, aspergillosis develops when susceptible individuals breathe in (inhale) Aspergillus spores. (For more information on this disorder, choose “aspergillosis” as your search term in the Rare Disease Database.)
There many different disorders, infections or conditions that may have symptoms similar to those found with aspergillosis. These include nocardiosis; fusariosis; anthrax; pseudallescheriasis; cavernous sinus thrombosis; sinusitis; bacterial orbital cellulitis; Churg-Strauss syndrome; granulomatosis with polyangiitis (Wegener granulomatosis); pulmonary eosinophilia; acute respiratory distress syndrome; tuberculosis; lung cancer; or fungal, bacterial or viral pneumonia. For more information, choose the specific disorder or condition name as your search term in the Rare Disease Database.
A diagnosis of mucormycosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis of mucormycosis is challenging because the symptoms are common to many conditions including other types of infection. A diagnosis is made by identifying mold in affected tissue and sometimes can be confirmed by a test called a fungal culture. A prompt diagnosis is important so treatment can begin as early as possible.
A diagnosis of mucormycosis can be suspected when affected individuals who have been identified as having a fungal infection do not respond to antifungal medications that target Aspergillosis, especially when Aspergillosis biomarkers are absent. Biomarkers for Aspergillosis include the Aspergillus galactomannan antigen. Antigens are substances that cause a response from the immune system; biomarkers are measurable substances that can indicate the presence of disease. There are no identified biomarkers for mucormycosis.
Clinical Testing and Workup
Doctors will take samples of affected tissue and a special doctor called a pathologist will study the tissue for changes caused by disease (histopathology). This can show the presence of mold. Samples can include fluid from the respiratory system or mucus coughed up from the lungs (sputum) if lung infection is suspected. Surgical removal of a small sample of skin tissue can be taken in cutaneous mucormycosis.
A tissue sample can then be taken and used for a fungal culture. A fungal culture is a procedure in which a sample of affected tissue is taken and sent to a laboratory and any fungus or similar organism discovered in the tissue is given time to grow. This test can determine the presence and type of fungal infection. However, sometimes a fungal culture does not reveal a fungal infection despite the presence of infection. Thus, a negative result on a fungal culture does not rule out mucormycosis.
If a histopathology study is positive for infection, but a fungal culture is negative, a test called polymerase chain reaction or PCR may be used. This test can identify the causative species of the infection. PRC is a test technique for identifying and making copies of specific segments of deoxyribonucleic acid (DNA). The test can identify tiny amounts of DNA including genetic material of infectious organisms like fungi. This test is not widely available and has not undergone clinical evaluation as to its effectiveness or appropriateness for diagnosing mucormycosis. Consequently, not all doctors recommend its use.
Imaging techniques such as computerized tomography (CT) scanning may be used to determine the exact location and extent of an infection. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. A CT scan may be taken of the lungs, sinuses, facial structures, or other areas of the body. In individuals with pulmonary mucormycosis, a CT scan of the lungs can reveal a reverse halo sign. This diagnostic clue is an area of tissue death (necrosis) that resembles ground glass on the film. It is suggestive of mucormycosis infection.
Treatment for mucormycosis will include antifungal medications. Antifungal medications inhibit the growth of and destroy fungal infections and are essential in controlling the spread of infection. The most commonly used medication is called amphotericin B. Initially, high doses of this medication are given intravenously. If an affected individual shows improvement, which can take several weeks, doctors may have the patient switch to oral antifungal medications, such as posaconazole or isavuconazole (Cresemba®). This is called step-down therapy. In 2015, the U.S. Food and Drug Administration (FDA) approved Cresemba for the treatment of adults with invasive mucormycosis.
If affected individuals do not respond to amphotericin B, or cannot tolerate the medication due to side effects, then posaconazole or isavuconazole may be given intravenously. This is called salvage therapy.
Surgery may be necessary to remove infected or dead tissue, damaged skin, and involved subcutaneous tissue. This is called surgical debridement and if the infection is significant, this can potentially lead to changes in the structure or shape of the affected area. Individuals with rhinocerebral mucormycosis can experience significant changes to facial appearance. Surgical debridement should be done as soon as the infection is confirmed. There are reports of people being cured of infection by the surgical removal of the infected lobe of the lung (lobectomy) because the infection began in this area and had not yet spread. Specific surgical recommendations will vary depending upon the exact location and extent of the infection.
Some affected individuals may receive adjunctive treatment with hyperbaric oxygen. Adjunctive treatment is a treatment given in addition to the initial, primary therapy. There have not been clinical trials on a large group of patients, but some small reviews on a small number of patients. Hyperbaric oxygen involves exposing the patient to pure oxygen in a pressure room or medical tube and has been effective in treating other types of serious infection. There is some research that shows that hyperbaric conditions can inhibit infection. However, there are risk with hyperbaric therapy including the need to move a patient out of intensive car where emergency intervention can be provided. More research is necessary to determine the long-term safety and effectiveness of hyperbaric oxygen and whether the therapy has a role in treating individuals with mucormycosis.
Doctors will also treat the underlying risk factor that can be associated with mucormycosis infection. Controlling underlying conditions is important in the treatment of this infection. This can include medications to increase the levels of white blood cells in people with neutropenia; insulin for people with uncontrolled diabetes; or medications called iron chelators that lowers the level of iron in the blood like and deferiprone for people with iron overload. It is extremely important that an iron chelator called deferoxamine is avoided because this medication actually promotes the growth and spread of mucormycosis in the body.
Mucormycosis is a serious, life-threatening infection that can prove fatal despite treatment. Many factors can influence treatment including the underlying condition associated with infection (e.g. hematologic cancer, diabetes, etc.), the exact location and extent of infection, how long until the proper diagnosis was made and when treatment was started, an individual’s age and overall health, and other factors.
Research is underway to better understand mucormycosis and how it interacts with an affected individual’s immune system. Hopefully, this can help lead to better, more effective treatments for this invasive fungal infection. Research is also underway to develop better diagnostic methods that can ensure quicker diagnosis of mucormycosis.
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