Highlights & Basics
- Mycobacterium avium complex (MAC) has variable presenting features including chronic cough, weight loss, and fevers.
- Increased incidence in patients with underlying lung disease, heavy smoking, and excessive alcohol consumption.
- HIV-infected patients with CD4 cell count <50 cells/microliter also at increased risk of infection.
- Diagnosis of pulmonary disease in non-HIV-infected individuals requires repeated isolation of the organism from respiratory secretions, in addition to compatible symptoms and radiographic presentation.
- Combination treatment with at least two drugs is essential.
Quick Reference
History & Exam
Key Factors
underlying lung disease
chronic productive cough
dyspnea
weight loss
fatigue
fever
lymphadenopathy
immunocompromised
hot tub use
Other Factors
age under 5 years
middle-to-old age
night sweats
abdominal pain
diarrhea
ronchi/crackles
hepatomegaly
splenomegaly
thin body habitus
pectus excavatum
scoliosis
systolic click and murmur
Diagnostics Tests
1st Tests to Order
CBC with differential
LFT
chest x-ray
sputum culture
blood culture
Other Tests to consider
high-resolution CT (HRCT) scanning
bone marrow aspirate for culture
bronchoscopy/bronchial lavage
lung biopsy
lymph node biopsy
Emerging Tests
polymerase chain reaction
Treatment Options
ongoing
pulmonary MAC
mild to moderate nodular bronchiectatic disease
cavitary disease
advanced (severe) disease or previously treated disease
disseminated MAC
disseminated MAC
advanced immunosuppression
Definition
Classifications
Disease syndromes associated with MAC
- Pulmonary disease
- Cervical lymphadenitis
- Disseminated disease
- Hypersensitivity pneumonitis
Vignette
Common Vignette 1
Common Vignette 2
Other Presentations
Epidemiology
Etiology
Pathophysiology
Diagnostic Approach
Pulmonary MAC
Disseminated MAC
Cervical lymphadenitis
Hypersensitivity pneumonitis
Risk Factors
History & Exam
Tests
Differential Diagnosis
Pulmonary tuberculosis
Differentiating Signs/Symptoms
- Difficult to clinically distinguish tuberculosis from MAC.
- History of tuberculosis exposure is helpful though not diagnostic.
Differentiating Tests
- Difficult to distinguish MAC fibrocavitary lesions from tuberculosis on lung imaging. However, MAC tends to have thinner-walled cavities, more contiguous extension of disease, and more pleural involvement.
- Smears will not distinguish between types of mycobacteria.
- Cultures are necessary to determine type.
Differentiating Signs/Symptoms
- Other types of NTM, such as M fortuitum or M cheloneae/abscessus, are difficult to distinguish based on symptoms.
Differentiating Tests
- Smears will not distinguish mycobacteria.
- Cultures are the most accurate way of making the distinction.
Differentiating Signs/Symptoms
- Clinically difficult to distinguish from disseminated MAC.
Differentiating Tests
- Histopathology is required to make the diagnosis of lymphoma.
- Cultures will be negative unless superimposed MAC infection present.
Histoplasmosis
Differentiating Signs/Symptoms
- Fungal infection commonly seen in immunosuppressed patients.
- Clinically difficult to distinguish from MAC.
Differentiating Tests
- Chest x-ray shows solitary pulmonary nodule that rarely cavitates.
- Diagnosed by culture, fungal stains, serologic tests for antibodies, and antigen detection.[36]
Blastomycosis
Differentiating Signs/Symptoms
- Fungal infection with similar clinical presentation to MAC.
- Commonly associated with skin lesions such as widespread papules or erythematous verrucous lesions.
Differentiating Tests
- Chest x-ray may have abnormal infiltrates.
- Sputum smear with fungal stains may show organism.
- Culture of sputum positive for fungus.
- Skin biopsy of lesion may show organism.
Cryptococcosis
Differentiating Signs/Symptoms
- Causes pulmonary, neurologic and disseminated disease.
- Pedunculated skin lesions.
- Central nervous system manifestations do not rule out disseminated MAC but are more suggestive of cryptococcosis.
Differentiating Tests
- Peripheral and cerebrospinal fluid cryptococcal antigen are very sensitive and specific tests.
Differentiating Signs/Symptoms
- Occurs in HIV patients in the absence of opportunistic infections or other identifiable causes of weight loss.
Differentiating Tests
- Clinical diagnosis of exclusion.
Sarcoidosis
Differentiating Signs/Symptoms
- Difficult to differentiate from pulmonary MAC and hypersensitivity pneumonitis.
Differentiating Tests
- Bilateral hilar lymphadenopathy on chest x-ray; lung biopsy demonstrates granulomatous tissue.
Criteria
- Respiratory symptoms that may be accompanied by additional constitutional signs and symptoms (cough, fatigue, fever, weight loss, hemoptysis)
- Reasonable exclusion of other diseases (e.g., tuberculosis, cancer, histoplasmosis) to explain condition.
- Nodular or cavitary opacities on chest radiograph, or
- Bronchiectasis with multiple small nodules on high-resolution computed tomography scan.
- At least two separate expectorated sputum samples, or
- At least one bronchial wash or lavage, or
- Transbronchial or other lung biopsy with granulomatous inflammation or positive acid-fast bacillus stain with positive culture for nontuberculous mycobacteria (NTM) from the biopsy or sputum/bronchial washings, or
- From usually sterile extra pulmonary site.
Screening
Patients with cystic fibrosis
Treatment Approach
MAC pulmonary disease
- With localized disease, especially upper lobe cavitary disease
- Who failed to convert the sputum culture to negative after 6 months of continuous medical therapy
- Who cannot tolerate medical therapy.
MAC disseminated disease
MAC lymphadenitis
MAC hypersensitivity pneumonitis
Macrolide-resistant MAC
Treatment Options
pulmonary MAC
mild to moderate nodular bronchiectatic disease
combination antimycobacterial therapy
Primary Options
- azithromycin
500 mg orally three times weekly
or
- clarithromycin
1000 mg orally (immediate-release) three times weekly
AND
- ethambutol
25 mg/kg orally three times weekly
AND
- rifampin
600 mg orally three times weekly
or
- rifabutin
300 mg orally three times weekly
- azithromycin
Comments
- For MAC pulmonary disease, treatment recommendations take into consideration the severity of disease as well as the radiographic appearance.
- Patients will require treatment until sputum cultures are consecutively negative for at least 12 months.[38]
- Older patients or patients who require long-term (6 months or longer) therapy may require lower doses.
- Treatment of macrolide-resistant MAC disease should only be done in consultation with a specialist, as management of these patients is complex. Guidelines suggest that extensive use of additional agents before referral to a specialist may compromise the patient's chance for an optimal therapeutic response; therefore, prompt referral is important.[38]
lobectomy/pneumonectomy
Comments
- May be considered in patients with localized disease, especially upper lobe cavitary disease; patients who failed to convert the sputum culture to negative after 6 months of continuous medical therapy; or patients who cannot tolerate medical therapy.
cavitary disease
combination antimycobacterial therapy
Primary Options
- azithromycin
250-500 mg orally once daily
or
- clarithromycin
500 mg orally (immediate-release) twice daily
AND
- ethambutol
15 mg/kg orally once daily
AND
- rifampin
10 mg/kg orally once daily, maximum 600 mg/day
or
- rifabutin
AND
- streptomycin
10-15 mg/kg intravenously/intramuscularly once daily; or 15-25 mg/kg intravenously/intramuscularly three times weekly; adjust dose according to serum streptomycin level
or
- amikacin
10-15 mg/kg intravenously once daily; or 15-25 mg/kg intravenously three times weekly; adjust dose according to serum amikacin level
- azithromycin
Comments
- For MAC pulmonary disease, treatment recommendations take into consideration the severity of disease as well as the radiographic appearance.
- For patients with cavitary disease, daily therapy with azithromycin or clarithromycin plus ethambutol plus rifampin or rifabutin is recommended. Azithromycin has fewer drug interactions and may be better tolerated than clarithromycin.
- Patients will require treatment until sputum cultures are consecutively negative for at least 12 months.[38]
- Older patients or patients who require long-term (6 months or longer) therapy may require lower doses.
- Treatment of macrolide-resistant MAC disease should only be done in consultation with a specialist, as management of these patients is complex. Guidelines suggest that extensive use of additional agents before referral to a specialist may compromise the patient's chance for an optimal therapeutic response; therefore, prompt referral is important.[38]
lobectomy/pneumonectomy
Comments
- May be considered in patients with localized disease, especially upper lobe cavitary disease; patients who failed to convert the sputum culture to negative after 6 months of continuous medical therapy; or patients who cannot tolerate medical therapy.
advanced (severe) disease or previously treated disease
combination antimycobacterial therapy
Primary Options
- azithromycin
250-500 mg orally once daily
or
- clarithromycin
500 mg orally (immediate-release) twice daily
AND
- ethambutol
15 mg/kg orally once daily
AND
- rifampin
10 mg/kg orally once daily, maximum 600 mg/day
or
- rifabutin
AND
- streptomycin
10-15 mg/kg intravenously/intramuscularly once daily; or 15-25 mg/kg intravenously/intramuscularly three times weekly; adjust dose according to serum streptomycin level
or
- amikacin
10-15 mg/kg intravenously once daily; or 15-25 mg/kg intravenously three times weekly; adjust dose according to serum amikacin level
- azithromycin
Comments
- For MAC pulmonary disease, treatment recommendations take into consideration the severity of disease as well as the radiographic appearance.
- For patients with advanced (severe) disease, daily therapy with azithromycin or clarithromycin plus ethambutol plus rifampin or rifabutin is recommended. Azithromycin has fewer drug interactions and may be better tolerated than clarithromycin. For patients with advanced (severe) disease, or where prior drug therapy has failed, the addition of intermittent amikacin or streptomycin to the regimen for the first 2 to 3 months of combination antimycobacterial therapy should be considered. These drugs may be given three times weekly (given the risk of ototoxicity).[38] [39]
- Treatment is continued until sputum cultures are consecutively negative for at least 12 months.
- Older patients or patients who require long-term (6 months or longer) therapy may require lower doses.
- Treatment of macrolide-resistant MAC disease should only be done in consultation with a specialist, as management of these patients is complex. Guidelines suggest that extensive use of additional agents before referral to a specialist may compromise the patient's chance for an optimal therapeutic response; therefore, prompt referral is important.[38]
amikacin liposomal inhalation
Primary Options
- amikacin liposomal inhaled
590 mg inhaled via nebulizer once daily
- amikacin liposomal inhaled
Comments
- If patients have not achieved negative sputum cultures after a minimum of 6 consecutive months of guideline-based therapy, amikacin liposomal inhalation may be added to the treatment regimen (i.e., daily therapy with azithromycin or clarithromycin plus ethambutol plus rifampin or rifabutin as per above).[38]
lobectomy/pneumonectomy
Comments
- May be considered in patients with localized disease, especially upper lobe cavitary disease; patients who failed to convert the sputum culture to negative after 6 months of continuous medical therapy; or patients who cannot tolerate medical therapy.
disseminated MAC
combination antimycobacterial therapy
Primary Options
- azithromycin
500-600 mg orally once daily
or
- clarithromycin
500 mg orally (immediate-release) twice daily
AND
- ethambutol
15 mg/kg orally once daily
- azithromycin
Comments
- Clarithromycin and ethambutol form the cornerstone of therapy for disseminated infection. Azithromycin can be substituted for clarithromycin where drug interactions and/or tolerability are an issue.[28]
- Treatment of macrolide-resistant MAC disease should only be done in consultation with a specialist, as management of these patients is complex. Guidelines suggest that extensive use of additional agents before referral to a specialist may compromise the patient's chance for an optimal therapeutic response; therefore, prompt referral is important.[27]
advanced immunosuppression
add third or fourth drug to combination regimen
Primary Options
- rifabutin
300 mg orally once daily
- rifabutin
- levofloxacin
500 mg orally once daily
- levofloxacin
- moxifloxacin
400 mg orally once daily
- moxifloxacin
- amikacin
10-15 mg/kg intravenously once daily, adjust dose according to serum amikacin level
- amikacin
- streptomycin
10-15 mg/kg intravenously/intramuscularly once daily, adjust dose according to serum streptomycin level
- streptomycin
Comments
- A third or fourth drug may be added in patients with advanced immunosuppression (CD4 count <50 cells/microliter) or high mycobacterial load, or in the absence of effective antiretroviral therapy. Options for a third or fourth drug may include rifabutin, a fluoroquinolone (e.g., levofloxacin or moxifloxacin), or an injectable aminoglycoside (e.g., amikacin or streptomycin).[28]
- Clinicians should be aware that fluoroquinolones have been associated with disabling and potentially irreversible musculoskeletal or nervous system adverse effects.[40] [41] In addition, the Food and Drug Administration has issued warnings about the increased risk of aortic dissection, significant hypoglycemia, and mental health adverse effects in patients taking fluoroquinolones.[42] [43]
antiretroviral therapy
Comments
- Initiate or continue antiretroviral therapy (ART) in HIV-infected patients.[28]
MAC lymphadenitis
localized disease
surgical excision
Comments
- Complete lymph node excision results in complete resolution of disease reported in 80% to 96% of patients.[44]
extensive disease; poor surgical response
combination antimycobacterial therapy
Primary Options
- clarithromycin
500 mg orally (immediate-release) twice daily
and
- rifampin
600 mg orally once daily
and
- ethambutol
15 mg/kg orally once daily
- clarithromycin
Comments
- If extensive disease, or poor response to surgical therapy, antimycobacterial therapy can be initiated.[27]
- Treatment of macrolide-resistant MAC disease should only be done in consultation with a specialist, as management of these patients is complex. Guidelines suggest that extensive use of additional agents before referral to a specialist may compromise the patient's chance for an optimal therapeutic response; therefore, prompt referral is important.[27]
MAC hypersensitivity pneumonitis
corticosteroidÂ
Primary Options
- prednisone
1-2 mg/kg/day orally
- prednisone
Comments
- Use of corticosteroids may shorten recovery time and improve gas exchange.
Prevention
Primary Prevention
Secondary Prevention
Follow-Up Overview
Prognosis
Monitoring
Complications
Citations
Griffith DE, Aksamit T, Brown-Elliott BA, et al. 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.[Abstract][Full Text]
Daley CL, Iaccarino JM, Lange C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Clin Infect Dis. 2020 Aug 14;71(4):e1-36.[Abstract][Full Text]
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6. Rickman OB, Ryu JH, Fidler ME, et al. Hypersensitivity pneumonitis associated with Mycobacterium avium complex and hot tub use. Mayo Clin Proc. 2002 Nov;77(11):1233-7.[Abstract]
7. Akram SM, Attia FN. Mycobacterium avium intracellulare. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Jan 2020 [internet publication].[Abstract][Full Text]
8. O'Brien RJ, Geiter LJ, Snider DE. The epidemiology of nontuberculous mycobacterial diseases in the United States: results from a national survey. Am Rev Respir Dis. 1987 May;135(5):1007-14.[Abstract]
9. Joshi W, Davidson PM, Jones PG, et al. Non-tuberculous mycobacterial lymphadenitis in children. Eur J Pediatr. 1989 Aug;148(8):751-4.[Abstract]
10. Horsburgh CR, Selik RM. The epidemiology of disseminated nontuberculous mycobacterial infection in the acquired immunodeficiency syndrome (AIDS). Am Rev Respir Dis. 1989 Jan;139(1):4-7.[Abstract]
11. Tumbarello M, Tacconelli E, de Donati KG, et al. Changes in incidence and risk factors of Mycobacterium avium complex infections in patients with AIDS in the era of new antiretroviral therapies. Eur J Clin Microbiol Infect Dis. 2001 Jul;20(7):498-501.[Abstract]
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13. von Reyn CF, Maslow JN, Barber TW, et al. Persistent colonisation of potable water as a source of Mycobacterium avium infection in AIDS. Lancet. 1994 May 7;343(8906):1137-41.[Abstract]
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16. Tsang AY, Denner JC, Brennan PJ, et al. Clinical and epidemiological importance of typing of Mycobacterium avium complex isolates. J Clin Microbiol. 1992 Feb;30(2):479-84.[Abstract][Full Text]
17. Gray JR, Rabeneck L. Atypical mycobacterial infection of the gastrointestinal tract in AIDS patients. Am J Gastroenterol. 1989 Dec;84(12):1521-4.[Abstract]
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21. Vankayalapati R, Wizel B, Samten B, et al. Cytokine profiles in immunocompetent persons infected with Mycobacterium avium complex. J Infect Dis. 2001 Feb 1;183(3):478-84.[Abstract]
22. Newport MJ, Huxley CM, Huston S, et al. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med. 1996 Dec 26;335(26):1941-9.[Abstract][Full Text]
23. Dorman SE, Holland SM. Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection. J Clin Invest. 1998 Jun 1;101(11):2364-9.[Abstract][Full Text]
24. Haas DW, Lederman MM, Clough LA, et al. Proinflammatory cytokine and human immunodeficiency virus RNA levels during early Mycobacterium avium complex bacteremia in advanced AIDS. J Infect Dis. 1998 Jun;177(6):1746-9.[Abstract]
25. Engbaek HC, Vergmann B, Bentzon MW. Lung disease caused by Mycobacterium avium/Mycobacterium intracellulare. An analysis of Danish patients during the period 1962-1976. Eur J Respir Dis. 1981;62(2):72-83.[Abstract]
26. Prince DS, Peterson DD, Steiner RM, et al. Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med. 1989 Sep 28;321(13):863-8.[Abstract]
27. Griffith DE, Aksamit T, Brown-Elliott BA, et al. 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.[Abstract][Full Text]
28. US Department of Health and Human Services, Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. Feb 2020 [internet publication].[Full Text]
29. Uthman MM, Uthman OA, Yahaya I. Interventions for the prevention of mycobacterium avium complex in adults and children with HIV. Cochrane Database Syst Rev. 2013 Apr 30;(4):CD007191.[Abstract][Full Text]
30. De Francesco MA, Colombrita D, Pinsi G, et al. Detection and identification of Mycobacterium avium in the blood of AIDS patients by the polymerase chain reaction. Eur J Clin Microbiol Infect Dis. 1996 Jul;15(7):551-5.[Abstract]
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32. Gilks CF, Brindle RJ, Mwachari C, et al. Disseminated mycobacterium infection among HIV-infected patients in Kenya. J Acquir Immune Defic Syndr. 1995 Feb 1;8(2):195-8.[Abstract]
33. Hanak V, Kalra S, Aksamit TR, et al. Hot tub lung: presenting features and clinical course of 21 patients. Respir Med. 2006 Apr;100(4):610-5.[Abstract]
34. Sood A, Sreedhar R, Kulkarni P, et al. Hypersensitivity pneumonitis-like granulomatous lung disease with nontuberculous mycobacteria from exposure to hot water aerosols. Environ Health Perspect. 2007 Feb;115(2):262-6.[Abstract][Full Text]
35. Nightingale SD, Byrd LT, Southern PM, et al. Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J Infect Dis. 1992 Jun;165(6):1082-5.[Abstract]
36. Kurowski R, Ostapchuk M. Overview of Histoplasmosis. Am Fam Physician. 2002 Dec 15;66(12):2247-52.[Abstract][Full Text]
37. US Department of Health and Human Services, Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected children. 2019 [internet publication].[Full Text]
38. Daley CL, Iaccarino JM, Lange C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Clin Infect Dis. 2020 Aug 14;71(4):e1-36.[Abstract][Full Text]
39. 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.[Abstract][Full Text]
40. US Food and Drug Administration. FDA drug safety communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. 2016 [internet publication].[Full Text]
41. European Medicines Agency. Quinolone- and fluoroquinolone-containing medicinal products. Mar 2019 [internet publication].[Full Text]
42. US Food and Drug Administration. FDA reinforces safety information about serious low blood sugar levels and mental health side effects with fluoroquinolone antibiotics; requires label changes. Jul 2018 [internet publication].[Full Text]
43. US Food and Drug Administration. FDA drug safety communication: FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. Dec 2018 [internet publication].[Full Text]
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Key Articles
Referenced Articles
Guidelines
Diagnostic
Summary
Discusses the diagnostic approach for opportunistic infections, including infections with MAC, in HIV-infected adults and adolescents.Published by
Centers for Disease Control and Prevention; National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America
Published
2020
Summary
Discusses the diagnostic approach for opportunistic infections, including infections with MAC, in HIV-exposed and HIV-infected children.Published by
Centers for Disease Control and Prevention; National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America
Published
2019
Summary
If pulmonary MAC suspected on clinical and epidemiologic grounds, chest x-ray should be obtained.If chest x-ray findings suggestive, but no cavitations, high-resolution computed tomography (HRCT) scanning is recommended.Sputum evaluation with acid-fast bacillus stains and cultures, as well as Gram stain and cultures are required.Other diseases should be excluded.Published by
American Thoracic Society; Infectious Diseases Society of America
Published
2007
Treatment
Summary
Discusses the treatment of opportunistic infections, including infections with MAC, in HIV-infected adults and adolescents.Published by
Centers for Disease Control and Prevention; National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America
Published
2020
Summary
Discusses the management of opportunistic infections, including infections with MAC, in HIV-exposed and infected children.Published by
Centers for Disease Control and Prevention; National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America
Published
2019
Summary
Recommendations for the treatment and prevention of nontuberculous mycobacterial diseases.Published by
American Thoracic Society; Infectious Diseases Society of America
Published
2007
Summary
Recommendations for the treatment of nontuberculous mycobacterial pulmonary disease.Published by
American Thoracic Society (ATS), European Respiratory Society (ERS), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA)
Published
2020