NORD gratefully acknowledges Chris Kosmidis MD, PhD, Senior Lecturer, University of Manchester Hon. Consultant, National Aspergillosis Centre, Manchester University NHS Foundation Trust, for assistance in the preparation of this report.
The symptoms of aspergillosis vary depending upon the specific form of the disorder present. The lungs are usually affected. Aspergillosis can present as an allergic reaction, an isolated finding affecting a specific area of the body (e.g., the lungs, sinuses or ear canals), or as an invasive infection that spreads to affect various tissues, mucous membranes or organs of the body.
ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
This form of aspergillosis usually occurs in individuals with long-standing asthma or cystic fibrosis. It is an allergic reaction to the breathing in (inhalation) of the fungi spores. These spores set off an improper response from an individual’s immune system. Initial symptoms resemble those associated with allergies and usually include chronic wheezing, shortness of breath (dyspnea), and a general feeling of poor health (malaise). Fever can occur, but is not common. Allergic bronchopulmonary aspergillosis may also cause chest pain, a cough that brings up blood (hemoptysis) or brown-colored globs (plugs) of mucus, and an excess of certain white blood cells (eosinophilia). The infection usually does not spread to other areas, but can cause complications when diagnosis is delayed or it is undertreated including chronic widening (dilation) of the bronchial tubes (bronchiectasis) or severe, persistent asthma and loss of lung function.
A related condition is called severe asthma with fungal sensitization [SAFS]. It is characterized by severe, poorly-controlled asthma in the presence of allergy to Aspergillus or other molds, but without fulfilling the criteria for and with only mild symptoms of Aspergillus infection.
CHRONIC PULMONARY ASPERGILLOSIS
Chronic pulmonary aspergillosis is characterized by scarring (fibrosis) within the lungs and the gradual loss of lung tissue which causes the formation of empty spaces (cavitation), or the widening and growth (expansion) of existing spaces. There is also thickening of the membranes around the lungs (pleural thickening). The term chronic pulmonary aspergillosis describes several distinct patterns of disease, including: aspergilloma, Aspergillus nodule, chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis, and subacute invasive pulmonary aspergillosis. Chronic pulmonary aspergillosis can recur after treatment.
The most distinctive form of aspergillosis is the development of a fungal ball known as an aspergilloma. These growths consist of a tangled mass of fungus fibers, mucus, tissue debris, inflammatory cells, and blood clotting protein (fibrin). Aspergillomas form in air pockets or cavities found within the lungs that may have been formed from previous lung disease (e.g., tuberculosis or emphysema). Most affected individuals do not have any apparent symptoms (asymptomatic) for years. Symptoms that can develop include wheezing, shortness of breath, chest pain, a chronic cough, fatigue, a cough that brings up blood (hemoptysis), and unintended weight loss. Fever is rare unless individuals also have a bacterial infection. In some instances, hemoptysis can become severe, potentially causing suffocation (asphyxiation). An aspergilloma may remain the same size, but can shrink or resolve without treatment. In some cases, an aspergilloma may gradually grow larger and damage nearby lung tissue; if that happens, the condition is called chronic cavitary pulmonary aspergillosis.
An Aspergillus nodule is a tiny mass of infected tissue. These nodules can form in individuals with fully functioning immune systems (immunocompetent hosts). Affected individuals can develop one nodule or multiple nodules, often without the formation of empty spaces (cavitation). Many individuals do not develop symptoms (asymptomatic), but some individuals will develop a cough, chest infection, or worsening (exacerbation) of an existing lung condition such as asthma or chronic pulmonary obstructive disease.
Chronic Cavitary Pulmonary Aspergillosis
Individuals with this form of aspergillosis develop cavities or empty spaces within the lungs (cavitation), or experience the widening or growth (expansion) of existing cavities. About half of these individuals have an aspergilloma on x-ray or CT scan. They can experience unintended weight loss, a chronic cough that produces mucus, the coughing up of blood, fatigue, and shortness of breath. Less often, fever or night sweats can occur. Rarely, significant and extensive scarring (fibrosis) can occur. This is sometimes referred to as chronic fibrosing pulmonary aspergillosis.
Subacute Invasive Pulmonary Aspergillosis (Chronic Necrotizing Aspergillosis)
This form of aspergillosis, also known as semi-invasive aspergillosis, has many similarities with chronic cavitary pulmonary aspergillosis, but progresses more quickly, usually over 1-3 months; the reason is that it affects individuals with some degree of immunosuppression (e.g. people taking high doses of steroids). Patients with more severe immunosuppression (e.g. undergoing chemotherapy or receiving a transplant) would usually develop a more acute disease, invasive aspergillosis. Subacute invasive pulmonary aspergillosis shows a chronic, slowly progressive process that, unlike invasive aspergillosis, does not spread to other organ systems or the blood vessels (angioinvasion). In some affected individuals, an aspergilloma (fungal ball) may develop in a cavity created by the destruction of lung tissue by the original infection. General symptoms associated with this form of aspergillosis include fever, night sweats, a cough that brings up sputum, fatigue, a general feeling of poor health (malaise), and unintended weight loss. Affected individuals may also cough up blood or sputum; this can vary from mild to severe.
Invasive aspergillosis is the most severe form of aspergillosis and usually affects individuals with weakened immune systems or those who have received bone marrow or solid organ transplant. It is characterized by infection that starts in the lungs and then rapidly travels through the bloodstream to affect various organs of the body potentially including the brain, kidneys, heart and skin. The specific symptoms associated with invasive aspergillosis vary based upon the organ system(s) involved. Affected individuals often develop fever, chills, headaches, a cough that brings up blood (mild hemoptysis) or sputum, shortness of breath (dyspnea), and chest pain. Severe life-threatening complications can develop including shock, delirium, massive bleeding from the lungs, and inflammation of the trachea and bronchi (tracheobronchitis), which may cause airway obstruction. Organ failure (e.g., liver or kidney) can occur. If the infection spreads to the brain, seizures, intracranial bleeding, or inflammation of the membranes surrounding the brain (meningitis) can occur. If the central nervous system is involved, it can present with a stroke.
Additional Forms of Aspergillosis
Aspergillosis may occur as an isolated infection of individual areas such as the nail beds, eyes, skin, sinuses or ear canals. Infection of the ear canals can cause itchiness, pain and the drainage of fluid from the ears. Infection of the sinuses (allergic Aspergillus sinusitis) may cause a stuffy nose, runny nose, congestion, fever, facial pain and headache. An aspergilloma may form in the sinuses or the infection may spread to other areas including the brain (central nervous system aspergillosis). Aspergillosis of the sinuses is sometimes associated with bone loss of the facial bones.
Infection with Aspergillus may cause inflammation of the thin membrane (endocardium) lining the heart, a condition called endocarditis. This condition occurs when heart tissue is directly infected by Aspergillus during cardiac surgery (post-operative aspergillosis). Individuals with aspergillosis affecting the site of surgery have also been reported following eye (ophthalmologic) and dental surgery.
The skin can be affected, sometimes following trauma, through open surgical wounds or injury, or if the infection starts somewhere else in the body and spreads to the skin. The gastrointestinal system can also be involved and can cause inflammation of the appendix (appendicitis), abdominal pain, ulcers, and bleeding from the gastrointestinal tract.
Aspergillus can also cause an infection within the eye called endophthalmitis. This most often occurs after trauma or surgery to the eye, or by the mold traveling to the eye through the blood during invasive aspergillosis (hematogenous seeding). Endophthalmitis can cause redness and pain in the eye. There may be a white or yellow discharge that comes out of the eye. Vision can be affected as well and there may be an increased sensitivity to bright light (photosensitivity).
Aspergillosis is a fungal infection caused by certain types of mold. They are found throughout nature (ubiquitous) and can be found in the soil and decaying organic matter like decaying vegetation. They can be found indoors, especially in heating or cooling ducts or in insulation. There are about 180 species of Aspergillus, but only about 40 are known to associated with disease in humans.
Although they are found commonly throughout nature, these molds normally don’t cause problems. We all inhale the mold spores daily, but healthy individuals are able to promptly remove them from the lungs. However, in certain individuals such as people 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.
Allergic bronchopulmonary aspergillosis is more likely to occur in individuals who have asthma or cystic fibrosis. Forms of chronic pulmonary aspergillosis are more likely to occur in individuals who have had a previous lung disease including tuberculosis or chronic obstructive pulmonary disease (COPD), or a disorder that can affect the lungs like sarcoidosis. In addition, people who have had lung surgery in the past, e.g. for pneumothorax or lung cancer, can also develop chronic pulmonary aspergillosis.
Invasive aspergillosis is more likely to occur in individuals who have a weakened immune system including 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; individuals who are receiving chemotherapy; or 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. Certain rare disorders like chronic granulomatous disease can also cause impaired function of the neutrophils and a susceptibility to Aspergillus.
People who have recently undergone hematopoietic stem cell transplantation (HSCT) are at highest risk for invasive aspergillosis. 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.
Other conditions can increase the risk of developing aspergillosis include people in the late stages of 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; and traumatic injury including burns or other injury to the skin.
Some researchers have noted that genetics can play a role in the development of aspergillosis. Researchers speculate that certain genes may make some individuals more likely to develop an infection with Aspergillus. This is called having a ‘genetic predisposition’ to developing a disease. Some research has indicated that genes that have a role in innate immune functions may be involved in the development of chronic pulmonary aspergillosis in some people. Genetic factors have also been explored for allergic bronchopulmonary aspergillosis, and this form of infection is believed to result from several factors (e.g. genetic, immunologic, environmental) occurring together. Research is underway to determine what role genetics play in the development of various forms of aspergillosis.
Researchers have mapped the genome for a few specific types of Aspergillus. A genome is the complete genetic makeup of an organism and researchers hope that these genomes will lead them to novel treatment options and to a better understanding of the various differences between the different species of Aspergillus.
Aspergillosis 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. Mild cases may go undiagnosed. According to the medical literature, the incidence of aspergillosis is increasing. Aspergillosis has been reported all over the world. Allergic bronchopulmonary aspergillosis has been estimated to affect about 1-4 million people worldwide. Chronic pulmonary aspergillosis is estimated to affect about 3 million people worldwide. Invasive aspergillosis is uncommon. Many forms are rare. Aspergillosis can potentially affect individuals of any age.
A diagnosis of aspergillosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests such as bronchoscopy with biopsy, x-rays, antigen skin tests, tissue culture or blood tests. Allergic bronchopulmonary aspergillosis should be suspected in individuals with difficult to control asthma or cystic fibrosis.
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. Respiratory fluid can be obtained through a procedure called a bronchoalveolar lavage or BAL. During BAL, a narrow tube (bronchoscope) is slid down the windpipe into the lungs and a sterile solution is passed through the tube washing out (lavaging) cells. This fluid is collected and then the tube is removed, allowing the cells to be studied.
Surgical removal (biopsy) of affected lung tissue can also be performed. In order to obtain a lung sample, physicians may recommend a bronchoscopy or percutaneous needle biopsy. During a bronchoscopy, a physician inserts a bronchoscope through the mouth and down an affected individual’s throat and obtains a sample of tissue to be analyzed (biopsy). During percutaneous needle biopsy, a needle is passed through the skin and inserted directly into the lungs to remove a tissue sample. A biopsy may not always be feasible due to the risk of complications such as bleeding.
Along with histopathologic examination, a tissue sample can also 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. The advantage of this test is that it allows us to know which antifungal medications are active against the infection. However, sometimes a fungal culture does not reveal a fungal infection despite the presence of an infection. Thus, a negative result on a fungal culture does not rule out aspergillosis.
An Aspergillus antigen skin test can be used to screen for allergic bronchopulmonary aspergillosis. During this test, a physician will inject a needle into a specific area of the body. If the area becomes inflamed or irritated with 48-72 hours, the person has been exposed to the Aspergillus fungus. Alternatively, a blood test (Aspergillus specific IgE) can be used if the skin test is not available. If the test is positive, then an additional test (total IgE) is required to make the diagnosis of allergic bronchopulmonary aspergillosis).
A physician may also perform a blood test to determine whether any aspergillosis antibodies are present. Antibodies, also known as immunoglobulins, are specialized proteins produced by the body to combat invading microorganisms, toxins, or other foreign substances. Blood tests can also reveal galactomannan or beta-d-glucan, which are substances found in the cell wall of Aspergillus. These tests, called assays, can be performed on certain people at risk of infection. The galactomannan assay test can also be performed on fluid obtained from the lungs (BAL fluid). When either of these tests is positive, this is indicative of invasive aspergillosis. These tests can also be positive for chronic pulmonary aspergillosis, although a blood galactomannan test is usually negative for this form of aspergillosis. The beta-d-glucan test is also often positive in other conditions, so it is not very specific for Aspergillosis.
X-rays of the chest are taken to detect characteristic findings such as the presence of an aspergilloma in a lung cavity or the buildup of Aspergillus fungi in the lungs. More advanced imaging techniques such as computerized tomography (CT) scanning may be used to determine the exact location and extent of an infection. A CT scan can reveal an aspergilloma, or findings that are suggestive of allergic bronchopulmonary aspergillosis or invasive aspergillosis. 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, or other areas of the body.
The treatment of aspergillosis varies depending upon the specific type of aspergillosis present, the extent of the infection, an individual’s overall health, and other factors. Treatment options include watchful waiting, drug therapy, and surgery. The same treatments are used for children as for adults, however, there are differences including the dosage of medications. For some medications, the standard or most effective dosage for children is not known.
In individuals with an aspergilloma who do not exhibit symptoms, no therapy may be necessary and watchful waiting may be recommended. Watchful waiting means that an asymptomatic person will be periodically monitored by physicians to detect if symptoms develop (e.g. coughing up of blood) or if the infection spreads or worsens.
Treatment for aspergillosis will include antifungal medications. Antifungal medications inhibit the growth of and destroy fungal infections and are essential in controlling the spread of infection. The medication, voriconazole (Vfend®), has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of invasive aspergillosis. Voriconazole is a common antifungal medication. This medication can also be used to treat other forms of Aspergillus infection.
The antifungal medication, isavuconazole (Cresemba®), has also been approved by the FDA for the treatment of invasive aspergillosis. The antifungal medication, posaconazole (Noxafil®), has been approved by the FDA as a preventive (prophylactic) treatment against fungal infections in individuals with low levels of white blood cells called neutrophils (neutropenia). Another antifungal medication that can be used to treat aspergillosis is amphotericin B. It comes in different formulations, including Amphotericin B deoxycholate and Liposomal Amphotericin B (Ambisome®).
A different type of antifungal medication called caspofungin has been approved the FDA for the treatment of invasive aspergillosis in individuals who have not responded to standard therapies, or who cannot tolerate standard therapy. This is called salvage therapy.
Another antifungal medication called itraconazole has been used to treat certain affected individuals. This drug is not considered a frontline therapy for invasive aspergillosis, but can be used in chronic and allergic forms. It is often used in individuals who do not have severe or non-life-threatening infection. It has also been used in individuals who have first been treated with amphotericin B. Most antifungal medications have not been effective in treating aspergillomas, although some individuals have responded to long-term treatment with oral itraconazole. This medication should not be used in immune-compromised individuals.
Sometimes, doctors may recommend combination therapy in which more than one of these medications is used together; this is usually done when affected individuals are very unwell or do not respond to treatment with just one medication.
Bronchial artery embolization is a procedure that can be used to treat chronic, significant coughing up of blood (hemoptysis). This procedure involves putting a catheter through the skin into a blood vessel, usually in the going, advancing it to the bronchial arteries (arteries delivering oxygen via the blood to the lungs) and creating an artificial clot that restricts or completely stops the flow of blood. Unfortunately, this procedure is not always effective, and bleeding can recur.
Surgery may be used to treat certain complications of invasive aspergillosis including massive hemoptysis that doesn’t resolve following bronchial artery embolization, or localized infection that fails to respond to antifungal medications. A simple aspergilloma can also be removed surgically. Some affected individuals with underlying lung diseases may not be candidates for surgery or may be high-risk candidates. Surgery, often along with antifungal medications, can also be recommended when the sinuses, the gastrointestinal system, or the heart are infected.
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. Surgical debridement should be done as soon as the infection is confirmed. Specific surgical recommendations will vary depending upon the exact location and extent of the infection.
Infection of the ear canals may be treated by scarping out the infected tissue and ear drops of antifungal medications.
Individuals with allergic bronchopulmonary aspergillosis are treated with oral corticosteroids such as prednisone (inhaled steroids are ineffective). Corticosteroids are anti-inflammatory medications that suppress the immune system’s improper response to the Aspergillus infection. Some individuals may receive an antifungal medication along with corticosteroids such as itraconazole. Individuals who also have asthma require standard treatment for the asthma as well.
Aspergillosis is a serious infection that can, sometimes, be life-threatening despite treatment. Many factors can influence treatment including the underlying condition associated with infection (e.g. hematologic cancer, neutropenia, 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.
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