Welcome to the NORD Physician Guide to Nontuberculous Mycobacterial Lung Disease (NTM). The NORD Online Physician Guides are written for physicians by physicians with expertise on specific rare disorders. This guide was written by Leah Lande, MD, Division of Pulmonary and Critical Care Medicine, Lankenau Medical Center. (see acknowledgements for additional information).
NORD is a nonprofit organization representing all patients and families affected by rare diseases. The information NORD provides to medical professionals is intended to facilitate timely diagnosis and treatment for patients.
NTM are mycobacterial species that are ubiquitous in the environment, and are classified separately from Mycobacterium tuberculosis complex and Mycobacterium leprae. Most of the disease burden from NTM is due to chronic lung infections in immunocompetent individuals with or without underlying lung disease.
NTM pulmonary infection can occur in patients with underlying lung disease such as COPD, bronchiectasis, cystic fibrosis, primary ciliary dyskinesia and alpha-1 antitrypsin deficiency, and can also occur in individuals without any prior underlying lung disease
The American Thoracic Society and Infectious Disease Society of America have published joint guidelines outlining the diagnostic criteria for pulmonary NTM infection.
Specific treatment decisions will vary considerably depending on individual patient factors and antimicrobial susceptibility of the organisms.
What is Nontuberculous Mycobacterial Lung Disease (NTM)?
NTM are mycobacterial species that are ubiquitous in the environment, and are classified separately from Mycobacterium tuberculosis complex and Mycobacterium leprae. There are over 140 species of NTM that have been identified thus far 1,2. NTM have been found in household water and soils, and are likely causing human infection through environmental exposure 3,4,5.
Most of the disease burden from NTM is due to chronic lung infections in immunocompetent individuals with or without underlying lung disease. The most common species to cause chronic lung infections is M. avium complex (MAC) 6. Other species that can cause chronic lung infection include M. abscessus, M. kansasii, M. fortuitum, M. xenopi, M. malmoense, M. szulgai, and M. simiae. The relative prevalence of each of these species varies throughout different parts of the world 6.
In addition to pulmonary infection, NTM can also cause superficial lymphadenitis, skin and soft tissue infections, and disseminated disease in immunocompromised patients 6,7.
There are different predisposing factors for the different forms and species of NTM. Patients with cavitary MAC infection are often prior smokers with underlying COPD or patients with pre-existing structural lung disease. Patients 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 pectus excavatum, mitral valve prolapse, scoliosis, and heterozygous mutations in the cystic fibrosis transmemberane regulator gene 12,13,14. 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 15,16,17.
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 18,29,20,21. Marfan’s syndrome, hyper-IgE syndrome, and congenital contractural arachnodactyly have also been associated with pulmonary NTM disease 22,23,24.
NTM pulmonary infection can occur in patients with underlying lung disease such as COPD, bronchiectasis, cystic fibrosis, primary ciliary dyskinesia and alpha-1 antitrypsin deficiency, and can also occur in individuals without any prior underlying lung disease 8. It is not yet fully understood why only certain individuals who are exposed to NTM in the environment develop infection. In addition, the severity of infection and disease course is highly variable between individuals, and the reasons for this variability are also not well understood at this time.
The symptoms of NTM lung infection may include any of the following:
NTM most commonly cause two different clinical entities in the lung. The first is nodular bronchiectasis, usually a less severe form of disease, characterized by interstitial tree-in-bud infiltrates on chest CT scan, often involving the right middle lobe and lingula. The second is cavitary disease, often involving the upper lobes, and characterized by more progressive and severe disease.
Less commonly, NTM can present as a solitary pulmonary nodule 9 or as a hypersensitivity pneumonitis in response to an intense inhalational exposure to MAC organisms, also known as “hot tub lung” 10,11.
The American Thoracic Society and Infectious Disease Society of America have published joint guidelines outlining the diagnostic criteria for pulmonary NTM infection 6. These guidelines require that a patient meet clinical, radiographic, and microbiologic criteria to establish a diagnosis of NTM pulmonary disease:
NTM 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 liquid media, and 2-4 weeks to grow in solid media. Once growth is evident, nucleic acid probes can be performed for rapid identification of M. tuberculosis, M. kansasii and MAC. [see figure 1]
The decision regarding whether to treat a patient with NTM pulmonary infection can sometimes be difficult. The potential risks of adverse effects of treatment must be weighed against the patient’s symptoms and severity of disease. If the decision is made not to treat, the patient should be monitored closely for disease progression. Antimicrobial regimens for the most common species of NTM are outlined below. Specific treatment decisions will vary considerably depending on individual patient factors and antimicrobial susceptibility of the organisms. Treatment should be continued for 12 months following conversion of sputum cultures to negative.
Treatment of MAC
2007 ATS/IDSA guidelines for treatment include use of all 3 of the following drugs, either 3 times per week or daily, depending on disease severity and presence of cavitary disease 6:
For nodular bronchiectatic MAC pulmonary disease (3 times per week regimen):
For cavitary or severe nodular bronchiectatic MAC disease (daily regimen):
*The 2007 ATS/IDSA statement recommendations do suggest that macrolide susceptibility testing be performed on isolates from patients in whom therapy is indicated 6. Antibiotic susceptibility testing is reliable only for macrolides and amikacin, in which MICS have been shown to correlate with in vivo response 6,25.
For patients with severe disease or with macrolide resistant isolates, consideration should be given to the addition of IV amikacin or IM streptomycin (10-15mg/kg 3x/week) for the first 8-12 weeks of therapy. Lower doses of 5-8mg/kg should be considered in patients older than 50 years old, whose weight is <50kg, or whose duration of injectable therapy is extended beyond 8-12 weeks. The use of inhaled amikacin can also be considered.
For patients who are intolerant of any of the above medications or with macrolide resistant isolates, the addition of Clofazimine 50-100mg daily can be considered as a part of a multi-drug regimen for treatment of MAC. Clofazimine is generally well tolerated, but can result in skin discoloration in up to 60% of patients. Currently, clofazimine is available in the United States for the treatment of MAC disease only with an IND application to the FDA for each patient.
Table 1 – Potential drug toxicities from the most commonly used medications for MAC infection
Monitoring for drug toxicity should include appropriate bloodwork, and regular auditory testing and ophthalmologic exams.
Treatment of M. kansasii
Treatment of Rapid Growers/M. abscessus
M. abscessus, M. chelonae and M. fortuitum are resistant to Isoniazid, Ethambutol and Rifampin, but are susceptible to various different antibiotics, including macrolides, amikacin, cefoxitin, imipenem, doxycycline, sulfonamides, and fluoroquinolones. Susceptibility testing must be performed on all clinically significant isolates, as antibiotic sensitivity patterns will vary between different isolates.
M. fortuitum and M. abscessus subspecies abscessus contain an inducible macrolide resistance (erm) gene, which can result in acquired macrolide resistance in these organisms after they are exposed to a macrolide. In order to detect this resistance, the isolate needs to be incubated for 14 days with a macrolide prior to determining the MIC for the macrolide 26,27.
Antimicrobial regimens should be based on drug susceptibility testing for individual isolates. Table 2 lists antibiotic options that may be considered.
Table 2. Antibiotic Regimens for Treatment of Rapidly Growing NTM
Non-pharmacologic treatment of pulmonary NTM disease
Monitoring for drug toxicity should be performed based on the potential adverse effects of the treatment regimen which is chosen. This may include monitoring of renal function (aminoglycosides), hepatic panel (macrolides), complete blood count (cefoxitin, sulfonamides) and auditory or vestibular testing (aminoglycosides and macrolides).
Patients with localized bronchiectasis, cavitary disease, or refractory hemoptysis may be considered for surgical resection of the involved area.
In addition to medications, the following modalities are also essential to proper care of patients with NTM lung disease:
Information on current clinical trials is posted at www.clinicaltrials.gov
All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
Insmed is conducting a randomized, phase III, open-label study to evaluate the effectiveness of liposomal Amikacin for inhalation (LAI) when added to multi-drug regimen in individuals with NTM lung infection caused by mycobacterium avium complex (MAC). The clinical study, being conducted in 31 locations, will evaluate the benefits of adding LAI to current treatment regimens and also help in understanding side effects LAI may cause in patients with MAC lung infection:
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
NORD does not endorse or recommend any particular studies.
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Leah Lande, MD
NORD is grateful to Dr. Lande for her authoring of this Physician’s Guide.
This NORD Physician Guide was made possible by an educational grant from Insmed.
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