NORD gratefully acknowledges Leah Lande, MD, Division of Pulmonary and Critical Care Medicine, Lankenau Medical Center, Associate Program Director, Pulmonary and Critical Care Fellowship Program, Clinical Assistant Professor, Lankenau Institute for Medical Research, Clinical Assistant Professor of Medicine, Jefferson University Medical College, for assistance in the preparation of this report.
Nontuberculous mycobacterial (NTM) lung disease is a general term for a group of disorders characterized by exposure to specific bacterial germs known as mycobacteria. These germs are found in the water and soil and are common throughout the environment as a whole. They usually do not cause illness. The term ‘nontuberculous’ is used to differentiate these disorders from the mycobacterium that cause tuberculosis (i.e. mycobacterium tuberculosis complex). These disorders also exclude Mycobacterium leprae, the mycobacterium that causes leprosy. In NTM disorders, the severity of infection and the disease course can vary greatly from one person to another. The most common symptoms include a persistent cough, fatigue, weight loss, night sweats, and occasionally shortness of breath (dyspnea) and coughing up of blood (hemoptysis). Less often, NTM infection can cause skin or soft tissue infections or infection and inflammation of the lymph nodes (lymphadenitis). Most evidence indicates that these infections are not transmitted from one person to another, but are acquired from the environment. NTM lung disease most commonly affects people with an underlying lung disease such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis, primary ciliary dyskinesia, and alpha-1-antitrypsin disease, but individuals with no prior history of lung disease can also be affected. Less severe infections may not require treatment. In other cases, the infection can become chronic requiring ongoing treatment.
The symptoms and severity can vary greatly from one person to another. The reason for this variability is not fully understood. Chronic lung infection is the most common complication affecting approximately 94% of individuals. The symptoms are usually nonspecific and similar to the symptoms seen in other lung or respiratory infections. Such symptoms include cough, fatigue, shortness of breath (dyspnea), coughing up of blood (hemoptysis), excessive mucus (sputum) production, fever, night sweats, loss of appetite, and unintended weight loss. Wheezing and chest pain may also occur. Affected individuals may experience recurrent respiratory infections. In some cases, these infections can cause progressive damage to the lungs and, eventually, the lungs will not function as well as they should (impaired lung function).
There are two main clinical presentations for NTM infection, which means that the symptoms and signs associated with this disorder are expressed in two specific ways. The less severe form is known as nodular bronchiectasis, in which the airways of the lungs become damaged, and subsequently dilate and become scarred. The airways can lose their ability to clear mucus and the mucus that accumulates within the airways can serve as a nutrient source and home for NTM, helping it to evade the immune system. Infiltrates can accumulate in the lungs particularly in the right middle lobe or the lingula, a small tongue-like projection from the upper left lobe of the lungs. Infiltrates is a nonspecific term describing substances that abnormally accumulate in the lungs or airways. Infiltrates can be pus, blood, or protein-rich fluid. Nodular bronchiectasis predominantly affects older women of Caucasian or Asian descent without a history of lung disease.
The second presentation is known as cavitary disease, in which scarring (fibrosis) or cavities form in the lungs (cavitation) particularly in the upper lobes of the lungs. This form is more severe and, if left untreated, can cause progressive cavitation and fibrosis, ultimately resulting in respiratory failure.
There are less common presentations of NTM infection. In some individuals, the disease will present as a single or multiple small masses in the lungs (single or multiple pulmonary nodules) or as hypersensitivity pneumonitis, a condition characterized by inflammation of the lungs after being exposed to NTM. In hypersensitivity pneumonitis cough, fever and shortness of breath are the most common symptoms.
Although pulmonary symptoms are the most common way NTM disease affects humans, these infections can also involve the skin, bones, and lymph nodes. Specific symptoms vary depending on the exact areas of the body affected. An infection can be widespread (disseminated) throughout the body and, without proper treatment, can prove fatal. Disseminated NTM infection occurs almost entirely in individuals whose immune system’s ability to fight infection is severely compromised or absent (immunocompromised individuals).
Nontuberculous mycobacterial lung disease is caused by infection with specific bacterial germs known as mycobacteria. These germs are commonly found throughout the environment. Most people do not become sick when exposed to these germs. More than 120 species of mycobacteria have been identified that can cause disease in humans. The most common are Mycobacterium avium complex or MAC. MAC encompasses three mycobacterial species known as M. avium,M. intracellulare, and M. chimaera. Collectively, these species account for approximately half of all mycobacterial infections.
Additional species that can cause infection in humans include M. abscessus, M. kansasii, M. fortuitum, M. xenopi, M. malmoense, M. szulgai, and M. simiae.
The underlying reason why some people become sick when exposed to these bacteria and other people do not is not fully understood. There may be certain risk or predisposing factors that, when present, make it more likely for infection to occur. However, in some people no predisposing or risk factor can be identified. Two main theories exist to explain individual susceptibility to NTM infection. Abnormalities in airway defenses or the ability of the airways to clear out normal secretions can lead to lung disease in individuals infected with NTM. In widespread (disseminated) NTM infection, an underlying problem with the immune system is suspected.
There are different predisposing factors for the different forms and species of NTM. Individuals with the cavitary form of infection are often prior smokers with underlying chronic obstructive pulmonary disease (COPD) or have pre-existing structural lung disease such as bronchiectasis.
Individuals with the nodular bronchiectatic form of MAC or with M. abscessus infection are often thin, middle aged or elderly females, and over half have no prior history of smoking or underlying lung disease. They may have other associated findings, including a sunken chest (pectus excavatum), abnormal curvature of the spine (scoliosis), improper closure of the valve between the upper left and lower left chambers of the heart (mitral valve prolapse) and heterozygous mutations in the cystic fibrosis transmemberane regulator gene (which means individuals have a mutation in one copy of the gene, rather than in both copies).
Individuals with cystic fibrosis (CF) and non-CF bronchiectasis are at increased risk for developing NTM infections, most commonly MAC or M. abscessus.
M. kansasii is more common in males and in individuals with underlying COPD or immune suppression from medications, HIV infection or malignancy.
Individuals with certain immune defects, including interferon gamma receptor deficiencies, auto-antibodies to interferon gamma, STAT-1 deficiency and GATA2 deficiency also have increased risk of developing NTM, including disseminated disease. Therapy with tumor necrosis factor alpha antagonist drugs, such as is used to treat rheumatoid arthritis and other connective tissue diseases, is also a risk factor for NTM infection. Marfan syndrome, hyper-IgE syndrome, and congenital contractural arachnodactyly have also been associated with pulmonary NTM disease. NORD has more information on some of these disorders (use the specific disorder name, as your search term in the Rare Disease Database).
In North America, the incidence of nontuberculous mycobacterial lung disease is rising, particularly among the elderly. Generally, NTM infection is more common in Caucasians, Asians and individuals with a compromised immune system. The incidence and prevalence rates reported in the medical literature varies and because many cases may go undiagnosed or misdiagnosed determining the true frequency of NTM infections in the general population is difficult.
A diagnosis of nontuberculous mycobacterial lung disease is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. However, the diagnosis can be challenging because the characteristic signs and symptoms are highly variable and nonspecific. A diagnosis of NTM includes ruling out other diseases such as tuberculosis or lung cancer.
The American Thoracic Society (ATS) and Infectious Disease Society of America (IDSA) have published joint guidelines (Griffith et al. 2007) outlining the diagnostic criteria for pulmonary NTM infection. The criteria used are a best fit for infection with Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium abscessus. These guidelines require that an affected individual meet clinical, radiographic, and microbiologic criteria to establish a diagnosis of NTM lung disease:
X-ray studies (e.g. chest x-ray) and high resolution computed tomography (HRCT) scans can be used to examine the lungs. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissues structures such as lung tissue. HRCT gives sharper, more detailed pictures of the lungs than traditional x-rays or conventional CT scanning.
A sputum culture is a test that can detect and identify bacteria that are infecting the lungs and various breathing passageways (airways). Sputum is a thick fluid produced within the lungs and breathing passageways of the respiratory tract, usually in response to infection or inflammation. Sputum is mainly made up of mucus and saliva. A sputum culture can be obtained directly from affected individuals by having them cough up a sample. A sputum sample can also be obtained through bronchoscopy. During bronchoscopy, a thin, flexible tube (bronchoscope) is inserted through the nose or mouth, allowing a physician to examine the throat, larynx, trachea and lower airways. During this procedure, a physician can also obtain a bronchoalveolar lavage (BAL), which is a deeper fluid sample from the alveoli (lung sacs) for examination. A bronchoscopy may be necessary for diagnosis in individuals who are unable to produce an adequate sputum sample.
During a lung biopsy, a small sample of affected lung tissue is surgically cut out, removed and studied under a microscope. In most cases, a lung biopsy is not necessary for a diagnosis of NTM infection.
NTM infections have traditionally been classified into rapidly growing and slowly growing mycobacteria. M. abscessus, M. chelonae, and M. fortuitum are rapidly growing mycobacteria, and usually grow in culture within one week. The slowly growing mycobacteria, which include the most common species, MAC, typically take 10-14 days to grow in a liquid medium, and 2-4 weeks to grow in solid medium. A liquid or solid medium is a liquid or gel designed to support the growth of microorganisms like bacteria. Once growth is evident, nucleic acid probes can be performed for rapid identification of M. tuberculosis, M. kansasii and MAC.
The decision to begin treatment for NTM infection is a challenging and difficult one. Treatment with a combination of antibiotic drugs (drug regimen) is the mainstay of therapy for these diseases. However, these drugs carry certain risks (side effects) and are often poorly tolerated, have a high cost, and require individuals to remain on the medications for a lengthy period of time. These risks must be weighed against the potential benefits for each individual based upon the severity of their disease and specific symptoms that are present. If a decision is made not to treat, then an affected individual should be closely monitored to promptly detect any progression of the infection.
Specific drug regimens will vary depending upon multiple factors including the susceptibility of the bacterial species in question to specific drugs as well as unique factors regarding the affected individual (age, overall health, specific symptoms, personal preference, and interactions with other medications). Treatment should be continued for 12 months after sputum cultures change from positive for infection to negative.
The ATS/IDSA guidelines (Griffith et al. 2007) include detailed treatment recommendations for individuals with NTM infections. These guidelines detail specific drug regimens including frequency, duration and dosage, monitoring for drug toxicity, and prophylactic treatment recommendations. The treatment regimens vary by species with the most important distinction being how to treat slow-growing versus rapid-growing NTM infection.
In specific cases such as in individuals with localized bronchiectasis, cavitary disease, or coughing up blood that does not improve with treatment (refractory hemoptysis), surgical removal of the affected tissue may be recommended. However, determining the best candidates and timing for surgical therapy is unknown.
There are additional measures that can be taken to help treat individuals with NTM infection. Various techniques that help to expel mucus from the lungs may be recommended for affected individuals. Such techniques include sterile, extra-salty water delivered as a mist (nebulized hypertonic saline), physical therapy of the chest, devices that loosen mucus in the airways (flutter devices, high frequency chest wall oscillation), a specific way of coughing that helps bring up mucus (huff cough), and aerobic exercise. Proper nutrition and weight maintenance are also important.
In 2018, Arikayce (amikacin liposome inhalation suspension) was approved for the treatment of lung disease caused by Mycobacterium avium complex (MAC) bacteria in a limited population of patients with the disease who do not respond to conventional treatment. Arikayce is manufactured by Insmed, Inc.
There are steps that affected individuals can take to lessen the chance of re-infection from the environment including the avoidance of hot-tubs, the avoidance of using tap water in humidifiers and CPAP machines, taking care in regard to environmental exposure to tap water and soil, and the use of specialized filtration systems in household plumbing. Since it is unknown whether individuals acquire NTM through inhalation (for example, from the shower spray) or from ingestion of tap water and subsequent reflux and aspiration of NTM-infected water into the lungs, consideration may be given to minimizing time spent in the shower and to boiling tap water prior to drinking.
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