Nontuberculous Mycobacterium Diseases

Definition and EtiologyTop

Mycobacterioses are caused by atypical mycobacteria: nontuberculous mycobacteria (NTM) and mycobacteria other than tuberculosis (MOTT). NTM species include Mycobacterium avium, M intracellulare, and M chimaera, rapidly growing mycobacterium (M fortuitum, M abscessus, and M chelonae), M xenopi, and M kansasii. Some species are associated with clinical disease, while other are rarely associated with disease. These strains are widely present in the environment, particularly in soil and water reservoirs. There is no evidence to suggest person-to-person transmission of NTM except for an isolated signal for a direct transmission of M abscessus between patients with cystic fibrosis in studies showing genetically distinct isolates in individuals attending shared clinics.Evidence 1Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the case report nature. Aitken ML, Limaye A, Pottinger P, et al. Respiratory outbreak of Mycobacterium abscessus subspecies massiliense in a lung transplant and cystic fibrosis center. Am J Respir Crit Care Med. 2012 Jan 15;185(2):231-2. PubMed PMID: 22246710. Geologic factors account for regional variability in incidence and speciation. At-risk groups include HIV-positive individuals, patients treated with anti–tumor necrosis factor alpha agents, individuals with a history of tuberculosis (TB), and patients with pneumoconiosis, cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease, or alcohol dependence. Clinical syndromes can also occur in patients with no preexisting lung disease or apparent indicators of immune dysfunction. NTM infection is not transmitted between humans and therefore is not a disease that requires reporting to public health authorities. Although NTM disease is not caused by infection with M tuberculosis complex, it is often considered in conjunction with TB since both diseases (1) overlap with respect to several clinical presenting features and therapeutic agents; (2) have specimens processed at a common mycobacteriology laboratory with expertise in acid-fast bacillus (AFB) smear, culture, drug-sensitivity testing, and speciation; (3) are often treated in a TB clinic setting by a health-care team with expertise in mycobacteriosis.

Clinical FeaturesTop

The clinical features are similar to TB and typically include chronic, productive cough, sputum production (with or without hemoptysis), asthenia, and less frequently fever and sweating. The NTM diseases also yield specimens with similar laboratory characteristics to TB, including positive AFB stain and necrotizing granuloma formation. Nucleic acid amplification tests are a rapid method of differentiation between the two conditions; however, the gold standard for identification is culture.

The lesions are predominantly located in the lungs, although other sites include lymph nodes, skin, and bone/joint. In some cases, multiple organs are involved. In patients who are not significantly immunocompromised, pulmonary NTM may be associated with 2 patterns. One pattern is of multiple small nodules, bronchiectasis, and tree-in-bud densities (mainly in the right middle lobe or lingula) visible on high-resolution computed tomography (HRCT) of the chest, often found in middle-aged women without preexisting lung disease. The second pattern with cavitation in the upper lobes often occurs in the setting of preexisting lung disease such as chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, and other abnormalities in pulmonary structure and mucus clearance. Patients with a single nodule or few nodules have no symptoms.

DiagnosisTop

NTM organisms can be isolated from pulmonary specimens due to contamination, colonization, or disease. Clinical, radiographic, and microbiologic criteria are all equally important and all 3 must be met in order to make a diagnosis of NTM disease.

1. Clinical criteria:

1) Pulmonary symptoms (cough, sputum, hemoptysis, chest pain, dyspnea) and/or systemic symptoms (fever, weight loss, fatigue), and

2) Exclusion of other potential causes (such as M tuberculosis complex, other respiratory infections, sarcoidosis, malignancy).

3) Progressive symptoms, which increase the likelihood of an NTM disease.

2. Radiology:

1) Chest radiograph: Nodular or cavitary opacities; or

2) Computed tomography (CT) of the chest: Bronchiectasis with multiple small nodules or lung cavitation, or air space disease (consolidation with ground-glass opacification).

3. Microbiologic criteria:

1) Positive culture result from at least 2 sputum samples collected on separate occasions; or

2) Positive culture result from at least 1 bronchial wash or lavage; or

3) Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) and positive culture of NTM, or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and 1 or more sputum or bronchial washings that are culture-positive for NTM.

TreatmentTop

Drug therapy for NTM lung diseases is not recommended for all patients. The decision to treat should be based on an individual assessment of the risks and benefits of therapy. Progression of clinical symptoms with compatible radiographic findings increases the likelihood of disease and may be an indication for a stronger recommendation for drug therapy. The long treatment period required to achieve a clinical effect is often poorly tolerated due to adverse effects and/or toxicities. Clinical outcomes for pulmonary NTM are suboptimal compared with treatment outcomes for M tuberculosis complex. Consultation with an expert in NTM disease is suggested, especially in complex cases where there is uncertainty about diagnosis of the disease, treatment indications, or management of drug therapy.

General principles of treatment:

1) Asymptomatic patients with a single or small number of randomly distributed incidental lung nodules due to NTM generally should not be treated unless there is significant radiographic progression with the development of symptoms.Evidence 2Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and indirectness. Behr M, Jarand J, Marras T. Nontuberculous Mycobacteria. In: Menzies D, ed. Canadian Tuberculosis Standards (7th edition). Canadian Lung Association, 2013:273-91. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/tb-canada-7/assets/pdf/tb-standards-tb-normes-pref-eng.pdf.

2) Combination therapy with 3 or more drugs is recommended for the treatment of NTM disease. Macrolides are an important component included in drug regimens for many of the common NTM species. Patients with repeated isolation of NTM should not receive macrolide monotherapy for treatment of bacterial infections or for treatment of NTM, as this may foster resistance to this class of drugs, thereby limiting efficacy of future NTM treatment.Evidence 3Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and indirectness. Behr M, Jarand J, Marras T. Nontuberculous Mycobacteria. In: Menzies D, ed. Canadian Tuberculosis Standards (7th edition). Canadian Lung Association, 2013:273-91. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/tb-canada-7/assets/pdf/tb-standards-tb-normes-pref-eng.pdf. Griffith D, Aksamit T, Winthrop K, et al. An official ATS/ISDA statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367-416. http://www.atsjournals.org/doi/pdf/10.1164/rccm.200604-571ST. Griffith DE, Aksamit T, Brown-Elliott BA, et al; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007 Feb 15;175(4):367-416. Review. Erratum in: Am J Respir Crit Care Med. 2007 Apr 1;175(7):744-5. Dosage error in article text. PubMed PMID: 17277290.

3) Drug choices are generally species-specific (Table 1). Evidence to support the recommended treatment regimens to target the various NTM species is weak to moderate. Data to correlate results from drug-susceptibility testing with clinical response to treatment is lacking, except for identification of macrolide resistance in MAC and rifampin (INN rifampicin) resistance in M kansasii. For M abscessus, susceptibility testing against macrolides and a wider panel of antibiotics may be used as a guide for treatment.Evidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data and indirectness. Haworth CS, Banks J, Capstick T, et al. British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). Thorax. 2017 Nov;72(Suppl 2):ii1-ii64. doi: 10.1136/thoraxjnl-2017-210927. Review. PubMed PMID: 29054853. Nebulized amikacin may be considered as an alternative to a parenteral aminoglycoside for longer-term therapy for M avium, M xenopi, and M abscessus.Evidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and imprecision. Olivier KN, Griffith DE, Eagle G, et al. Randomized Trial of Liposomal Amikacin for Inhalation in Nontuberculous Mycobacterial Lung Disease. Am J Respir Crit Care Med. 2017 Mar 15;195(6):814-823. doi: 10.1164/rccm.201604-0700OC. PubMed PMID: 27748623; PubMed Central PMCID: PMC5363966.

4) The duration of treatment is ≥12 months from the first negative culture result; and when mycobacteriosis is diagnosed based on cultures of a material other than sputum, up to 18 months. Isolated pulmonary lesions and involved lymph nodes may be treated by surgical resection.

5) Monitoring while on drug therapy is important to assess clinical response, adverse effects, and drug toxicities. Medication schedules and regimens require frequent modifications if treatment is poorly tolerated or ineffective. Practices regarding regular monitoring for specific adverse reactions, such as liver toxicity (rifampin), optic neuritis (ethambutol), or nerve VIII and renal injury (aminoglycosides), are variable. Most clinicians recommend at least monthly monitoring of parameters appropriate to drug selection, which may include transaminases, visual assessment with an ophthalmologist or optometrist, audiograms, and/or creatinine levels.

TablesTop