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Pulmonary aspergillosis and HIV/AIDS

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Related Terms
  • Acquired immune deficiency syndrome, acquired immunodeficiency syndrome, ABPA, AIDS, allergic bronchopulmonary aspergillosis, allergic reaction, allergic response, aspergilloma, aspergillosis, Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Aspergillus pneumonia, cavitary disease, chronic necrotizing Aspergillus pneumonia, CNAP, cystic fibrosis, fungal infection, fungal spores, fungus, HIV, human immunodeficiency syndrome, hypersensitivity reaction, hypersensitivity response, hyphae, IgE, immunocompromised, immunodeficiency, immunoglobulin, immunoglobulin E, invasive aspergillosis, mold infection, organ transplant, organ transplant recipient, pulmonary cavities, pulmonary infections, weakened immune system.

Background
  • The Aspergillus fungus causes aspergillosis pulmonary infections. Although there are more than 100 Aspergillus species, most human illnesses are caused by Aspergillus fumigatus and Aspergillus niger and, less frequently, Aspergillus flavus and Aspergillus clavatus.
  • The fungus that causes the infection is commonly found on dead leaves, stored grain, compost piles, and decaying vegetation. People are commonly exposed to the fungus, but it usually only causes infections in individuals who have weakened immune systems, such as HIV/AIDS patients.
  • The fungal spores are transmitted to humans when they are inhaled. Therefore, the infection primarily affects the lungs. However, if the patient is severely immunocompromised (as in HIV/AIDS or cancer patients), the infection may spread to other organs. In such cases, the infection may cause endophthalmitis (inflammation of the eye that is a medical emergency), endocarditis (infection of the lining of the heart), and abscesses in the heart muscle, kidney, liver, spleen, soft tissue, and bone.
  • There are four main types of aspergillosis: allergic bronchopulmonary aspergillosis (ABPA), chronic necrotizing Aspergillus pneumonia (CNAP), aspergilloma, and invasive aspergillosis.
  • According to the U.S. Centers for Disease Control and Prevention (CDC), aspergillosis is not considered an AIDS-defining illness (illness that indicates that the patient's condition has progressed to AIDS).

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography
  1. Centers for Disease Control and Prevention (CDC). . Accessed May 12, 2009.
  2. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002 Aug 8;347(6):408-15.
  3. HIV InSite. . Accessed May 12, 2009.
  4. Marr KA, Boeckh M, Carter RA, et al. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis. 2004 Sep 15;39(6):797-802. Epub 2004 Aug 27.
  5. Natural Standard: The Authority on Integrative Medicine. . Copyright © 2009. Accessed May 12, 2009.
  6. Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group. Medicine (Baltimore). 2000 Jul;79(4):250-60.

Causes
  • In general, aspergillosis rarely occurs in patients who have healthy immune systems.
  • The Aspergillus fungus causes aspergillosis pulmonary infections. Although there are more than 100 Aspergillus species, most human illnesses are caused by Aspergillus fumigatus and Aspergillus niger and, less frequently, Aspergillus flavus and Aspergillus clavatus.
  • The cells and tissues of Aspergillus hyphae (filaments that make up the body of a fungus) are distinct from other fungi. The hyphae have frequent septae that branch at 45-degree angles. The fungus is commonly found on dead leaves, stored grain, compost piles, and decaying vegetation.
  • Allergic bronchopulmonary aspergillosis (ABPA): An allergic reaction to the fungus is possible and most common among asthmatics or cystic fibrosis patients. The first time or several times after the body is exposed to an allergen, the immune system becomes sensitized. During this process, the body's white blood cells develop immunoglobulin E (IgE) antibodies to the fungus. Once sensitized, the antibodies quickly detect the fungus allergen when it enters the body. These antibodies trigger the release of chemical mediators, which cause allergy symptoms such as hives, rash, tearing eyes, and runny nose. When the hypersensitivity reaction is triggered, alveoli (tiny air sacs in the lung) become inflamed and their walls fill up with white blood cells.
  • Chronic necrotizing Aspergillus pneumonia (CNAP): Individuals who have underlying pulmonary diseases (including chronic obstructive pulmonary disease, interstitial lung disease, and previous chest surgery) and altered immune status due to chronic corticosteroid therapy, alcoholism, collagen vascular disease, or chronic granulomatous disease (inherited disorder that impairs phagocytic cells that normally kill bacteria that enters the body) have an increased risk of developing chronic necrotizing Aspergillus pneumonia (CNAP).
  • Aspergilloma: Aspergilloma typically develops in patients who have preexisting cavities in the lungs (abnormal spaces between the membranes that cover the lungs). Underlying causes of the cavitary disease may include tuberculosis or other necrotizing infections (flesh-killing infections), sarcoidosis (inflammation of the lymph nodes, liver, lungs, and spleen), cystic fibrosis, and emphysematous bullae (blisters under the skin). Aspergillomas may also develop in patients with invasive aspergillosis or chronic necrotizing Aspergillus pneumonia (CNAP).
  • Invasive aspergillosis: When a human host inhales the fungus spores, the organism enters the lungs. Macrophages (white blood cells that kill microorganisms that enter the body) and neutrophils (white blood cells that destroy foreign substances that enter the body) will engulf the invading fungus to prevent infection. However, many species of Aspergillus produce toxic metabolites that may prevent macrophages and neutrophils from engulfing them. Individuals who are taking corticosteroids or have immunodeficiencies (such as HIV/AIDS and chronic granulomatous disease) have impaired macrophage and neutrophil function, making it even more difficult to fight off the fungus. Consequently, patients who are immunocompromised are unable to fight off the invading fungus, and therefore, suffer from pulmonary infections.

Symptoms
  • Allergic bronchopulmonary aspergillosis (ABPA): Common symptoms include fever, inflamed airways, mucous plugs, blood in sputum, wheezing and cough. The pulmonary infiltrates may not be responsive to antibacterial therapy. Patients who have asthma may experience a worsening of asthmatic symptoms.
  • Chronic necrotizing Aspergillus pneumonia (CNAP): Patients who have chronic necrotizing Aspergillus pneumonia (CNAP) typically have an underlying disease like steroid-dependent chronic obstructive pulmonary disease (COPD). Symptoms are usually nonspecific and may include fever, night sweats, cough, and weight loss.
  • Aspergilloma: About 40-60% of patients with aspergilloma experience hemoptysis (blood in sputum caused by pulmonary bleeding), which may be severe and life threatening. Less common symptoms such as cough and fever may occur.
  • Invasive aspergillosis: Common symptoms of invasive aspergillosis include fever, cough, dyspnea (shortness of breath), tachypnea (rapid breathing), chest pain, hypoxemia (low levels of oxygen in the blood), and sometimes hemoptysis (blood in sputum).

Diagnosis
  • Allergic bronchopulmonary aspergillosis (ABPA):
  • General: The Cystic Fibrosis Foundation has developed criteria for diagnosing ABPA. A definitive diagnosis can be made if the patient has 1) worsening of symptoms, including cough, wheezing, increased sputum, and decreased pulmonary function; 2) there are elevated levels of (immunoglobulin) IgE (greater than 1,000 IU/mL or a greater than two-fold rise from baseline); 3) there is a positive serological test for Aspergillus; or 4) new infiltrates are detected on a chest X-ray or computerized tomography (CT) scan.
  • Skin test: A positive skin test may be conducted to determine if elevated levels of IgE are produced in response to the fungus. During the test, an area of the patient's skin is exposed to the allergen and observed for an allergic reaction. Positive results indicate that the patient is allergic to the fungus.
  • Blood test: A blood test may be performed to determine whether the fungus is present.
  • Imaging studies: A chest X-ray or computerized tomography (CT) scan may be performed to determine whether there are fungal infiltrates in the lungs.
  • Chronic necrotizing Aspergillus pneumonia (CNAP):
  • General: A definitive diagnosis of invasive aspergillosis or chronic necrotizing Aspergillus pneumonia depends on the demonstration of the organism in the lung tissue .
  • Sputum-induction for histopathologic testing: A sputum sample analysis can be conducted to determine whether a patient has CNPA. The patient will cough deeply, expelling material from the lungs into a sterile cup. The sample is then taken to a laboratory and placed in a medium under conditions that allow the fungus to grow. A positive culture will identify the disease-causing fungus. Sensitivity of a sputum analysis varies widely (50-90%), and depends on proficiency in using the technique and the experience of the laboratory.
  • Bronchoalveolar lavage (BAL): Bronchoalveolar lavage may be performed to determine whether patients have CNAP. During the procedure, a bronchoscope (thin, flexible tube) is passed through the mouth or nose into the lungs. Saline is then squirted into a small part of the lung and then collected for analysis. If Aspergillus fungus spores are present, a positive diagnosis is made. This procedure is performed when CNPA is strongly suggested, but the sputum sample is negative. The test has about 90% sensitivity and specificity, if performed correctly.
  • Aspergilloma:
  • Chest X-ray: A chest X-ray may detect a preexisting cavity in the lungs, usually in an upper lobe. This cavity may contain a solid mass called a fungus ball. This mass may move inside the cavity if the patient changes positions.
  • Computerized tomography (CT scan): A computerized tomography (CT) scan can provide a detailed image of the fungus ball. A CT scan can detect multiple aspergillomas in large cavities.
  • Invasive aspergillosis:
  • General: Definitive diagnosis of invasive aspergillosis or chronic necrotizing Aspergillus pneumonia depends on the demonstration of the organism in the lung tissue.
  • Sputum-induction for histopathologic testing: A sputum sample analysis can be conducted to determine whether a patient has aspergillosis. The patient will cough deeply, expelling material from the lungs into a sterile cup. The sample is then taken to a laboratory and placed in a medium under conditions that allow the fungus to grow. A positive culture will identify the disease-causing fungus. Sensitivity of a sputum analysis varies widely (50-90%), and depends on proficiency in using the technique and the experience of the laboratory.
  • Bronchoalveolar lavage (BAL): Bronchoalveolar lavage may be performed to determine whether patients have invasive aspergillosis. During the procedure, a bronchoscope (thin, flexible tube) is passed through the mouth or nose into the lungs. Saline is then squirted into a small part of the lung and then collected for analysis. If Aspergillus fungus spores are present, a positive diagnosis is made. This procedure is performed when aspergillosis is strongly suggested, but the sputum sample is negative. The test has about 90% sensitivity and specificity, if performed correctly.
  • The presence of elevated galactomannan (a major component of the Aspergillus cell wall) levels in bronchoalveolar lavage (BAL) fluid may also indicate invasive aspergillosis
  • Lung biopsy: An open lung biopsy is the most invasive procedure and has 100% sensitivity and specificity because it provides the greatest amount of tissue for diagnosis. However, this test is only conducted in rare cases when a bronchoscopy is nondiagnostic. The procedure is performed in a hospital while the patient is under general anesthesia. A tube is inserted through the mouth and into the airway that leads to the lungs. After cleaning the skin, the surgeon makes a cut in the chest area and removes a small piece of lung tissue. The wound is closed with stitches. A chest tube may be left in place for one to two days to prevent the lung from collapsing. The tissue sample is taken to a laboratory for a histological examination.
  • Chest X-ray: A chest X-ray may detect solitary or multiple nodules, cavitary lesions, or alveolar infiltrates in the lungs.
  • Computerized tomography (CT) scan: A computerized tomography (CT) scan may be helpful in the early diagnosis of aspergillosis. A characteristic halo image (an area of ground-glass infiltrates surrounding nodular densities) may be visible. During the later stages of the disease, the test may show a crescent of air surrounding nodules, which indicates cavitation.

Treatment
  • General: Treatment varies depending on the specific type of aspergillosis. HIV/AIDS patients should receive antiretroviral therapy to restore the body's immune system.
  • Allergic bronchopulmonary aspergillosis (ABPA): Oral corticosteroids, like prednisone (Deltasone®, Meticorten®, or Orasone®), are the standard treatment for ABPA. Treatment generally lasts about two weeks, followed by a three to six month tapering off period. Patients who experience recurrent or chronic ABPA have also been prescribed oral itraconazole in addition to corticosteroids.
  • Chronic necrotizing Aspergillus pneumonia (CNAP): Patients typically receive treatment with the antifungal voriconazole (Vfend®). Other antifungals, such as itraconazole (Sporanox®), caspofungin (Cancidas®), or amphotericin B formulations (Fungilin®, Fungizone®, Abelcet®, AmBisome®, Fungisome®, Amphocil®, Amphotec®), have also been used, but they are not as effective as voriconazole.
  • If the infection does not respond to antifungal therapy, surgical resection (removal of part of the lung) may be considered. Also, aspergillomas may occasionally form in areas of necrotizing pneumonia (pneumonia caused by inhaling foreign substances like vomit or food). These areas may bleed and often require surgical removal of tissues.
  • Aspergilloma: While surgical removal of the fungal ball is curative, it may not be possible in patients who have limited pulmonary (lung) function. Oral itraconazole (Sporanox®) may provide partial or complete resolution of aspergillomas in about 60% of patients. A medical procedure called intracavitary treatment has also been used in a small number of patients. During the procedure, CT-guided catheters, which are inserted with a needle, inject amphotericin alone or in combination with other drugs like acetylcysteine (Mucomyst® or Mucosil®) and aminocaproic acid (Amicar® or Cyklokapron®).
  • Bronchial artery embolization (insertion of a substance through a catheter into a blood vessel to stop bleeding) may be used for life-threatening hemoptysis (blood in the sputum) in patients who are unable to undergo surgery. Inserting a catheter into the bronchial artery requires a skilled and experienced radiologist because localizing the abnormal vessel(s) may be challenging.
  • Invasive aspergillosis: An antifungal called voriconazole (Vfend®) is the standard treatment for invasive aspergillosis. Amphotericin B (Fungilin®, Fungizone®, Abelcet®, AmBisome®, Fungisome®, Amphocil®, Amphotec®) formulations may be considered as a possible treatment before a diagnosis is confirmed in critically ill patients. Caspofungin (Cancidas®) has also been approved for treatment of invasive aspergillosis in patients who are not responding to other therapies.
  • Combination antifungal therapy has been used to treat patients whose condition worsens with use of just one drug. However, taking azole antifungals (Diflucan®, Nizoral® or Sporanox®) with amphotericin B (Fungilin®, Fungizone®, Abelcet®, AmBisome®, Fungisome®, Amphocil®, Amphotec®) is controversial because the azole antifungals decrease amphotericin-binding sites and may reduce its effectiveness.
  • If the infection does not respond to antifungal therapy, surgical removal of part of the lung may be considered. Also, aspergillomas may occasionally form in areas of necrotizing pneumonia (pneumonia caused by inhaling foreign substances like vomit or food). These areas may bleed and often require surgical removal.

Types of aspergillosis
  • Allergic bronchopulmonary aspergillosis (ABPA): Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitive reaction to A. fumigatus, which causes inflammation of the airways and air sacs of the lungs. This reaction usually occurs along with asthma and cystic fibrosis (genetic disorder of the mucus in the lungs that causes breathing problems). Allergic fungal sinusitis (inflammation of the sinuses caused by fungal exposure) may also occur. ABPA may worsen asthma symptoms. Repeated episodes of ABPA may cause widespread bronchiectasis (dilation of airway passages) and cause chronic fibrotic lung disease.
  • About 25% of asthmatics and 50% of patients who have cystic fibrosis are allergic to Aspergillus.However, only a few people develop ABPA. According to surveys and an ABPA registry, only 0.25-0.8% of asthmatics and about seven percent of patients with cystic fibrosis are estimated to have ABPA. The incidence of ABPA in people with asthma who are dependent on steroid inhalers or have associated central bronchiectasis is estimated to be between 7-10%.
  • Chronic necrotizing Aspergillus pneumonia (CNAP): Chronic necrotizing Aspergillus pneumonia (CNAP) is a rare condition that usually occurs in patients who have weakened immune systems. This condition is frequently associated with underlying lung disease, alcoholism, or long-term corticosteroid therapy. Since the condition usually is not discovered until an autopsy is conducted after the patient has died, the frequency of CNAP may be underestimated. Also, because CNAP is rare, it often remains unrecognized for weeks or months, allowing the fungus spores to multiply in the lungs. CNAP has a reported mortality rate of 10-40%. However, rates as high as 100% have been noted because it often remains undiagnosed for such a long time.
  • Aspergilloma: An aspergilloma is a fungus ball (mycetoma) that develops in a pre-existing lung cavity (abnormal space between the membranes that line the lungs). Underlying causes of the cavitary disease may include tuberculosis or other necrotizing infection, sarcoidosis (inflammation of the lymph nodes, liver, lungs, and spleen), cystic fibrosis, and emphysematous bullae (blisters under the skin). According to one survey of patients who had cavitary lung disease due to tuberculosis, 17% developed aspergilloma. The ball of fungus may move inside the cavity, but it does not enter the cavity wall. Aspergilloma may cause hemoptysis (blood in the sputum), which may be severe and life threatening.
  • Invasive aspergillosis: Invasive aspergillosis is a rapidly progressive, often fatal infection that occurs in patients who have extremely weakened immune systems. Patients who have undergone bone marrow transplants or solid organ transplants, those who are neutropenic (low levels of white blood cells called neutrophils), and patients with advanced AIDS or chronic granulomatous disease (inherited disorder that impairs phagocytic cells that normally kill bacteria that enters the body) are susceptible to invasive aspergillosis. The fungus spores invade the blood vessels and infiltrate the membranes that surround the lungs. The infection may spread to other organs, especially the central nervous system (CNS).
  • Invasive aspergillosis is estimated to occur in 5-13% of bone marrow transplant recipients, 5-25% of patients who have received heart or lung transplants, and 10-20% of patients receiving intensive chemotherapy for leukemia. Although there have been reports of invasive aspergillosis in patients who have healthy immune systems, it is extremely rare. Invasive aspergillosis is associated with a high rate of mortality (30-95%).

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