Continuing Education Activity

Mycobacterium avium complex consists of multiple nontuberculosis mycobacterial species (NTM), which cannot be distinguished in the microbiology laboratory and requires genetic testing.A newcomer to the Mycobacterium avium complex is the Mycobacterium paraintracellulare, identified in pulmonary infections in Southeast Asia in 2016. M. avium complex is the most common cause of nontuberculosis mycobacterial species infections in humans, and respiratory system is the most common site of infection. This activity reviews the presentation and pathophysiology of mycobacterium avium intracellulare and highlights the role of the interprofessional team in its management.

Objectives:

• Describe the pathophysiology of Mycobacterium avium intracellulare.
• Review the presentation of a patient with Mycobacterium avium intracellulare.
• Summarize the treatment of Mycobacterium avium intracellulare.
• Outline modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by Mycobacterium avium intracellulare.

Introduction

Mycobacterium avium complex consists of multiple nontuberculosis mycobacterial species (NTM), which cannot be distinguished in the microbiology laboratory and requires genetic testing. M. avium and Mycobacterium intracellular are the two original members of this complex, known for about a hundred years. Mycobacterium chimaera has been included in the M. avium intracellulare complex (2004). Some include Mycobacterium subspecies paratuberculosis in the My.avium complex as well. A newcomer to the Mycobacterium avium complex is the Mycobacterium paraintracellulare, identified in pulmonary infections in Southeast Asia in 2016.

M. avium was first isolated in chickens 1933 with a cavitary disease resembling tuberculosis. Human cases were identified decades later. M. avium complex is the most common cause of nontuberculosis mycobacterial species infections in humans, and respiratory system is the most common site of infection.[1][2][3]

Etiology

M. avium complex is a nonmotile, non-spore-forming, gram-positive acid-fast bacillus. M. avium complex is a nonchromogen and slow-growing and takes about 10 to 20 days to develop mature colonies. M. avium complex belongs to class III of the Runyon classification. M. avium grows best at 34.5 C, and Mycobacterium intracellulare grows best at 31.5  C. However, M. avium complex components can grow between 28 C to 38.5 C. Most M. avium can survive 49 C. Whereas, only 10% of M. intracellulare survive a temperature of 49 C. Mycobacterium scrofulaceum is similar to Mycobacterium avium complex in the biochemical properties and the same group. M. avium is composed of four named subspecies; these are, M. avium subspecies Avium (two strains), M. avium subspecies silvaticum, M. avium subspecies paratuberculosis, and M. avium subspecies hominissuis. It appears that the M. avium subspecies avium are responsible for pulmonary infections and the M. avium subtype hominissuis appears to be gastrointestinal in origin (6). M. avium subspecies paratuberculosis was identified in ruminants as a causative agent for Johne disease. Some have hypothesized and debated for decades that M. avium subspecies paratuberculosis is the etiological agent of Crohn disease in humans without strong evidence. A recent publication found, a high prevalence of M. avium subspecies paratuberculosis antibodies in inflammatory bowel diseases when compared to patients with noninflammatory bowel diseases, 64% vs. 9.7%. Live M. avium subspecies paratuberculosis was only isolated from two Chron's disease patients. M. avium subspecies paratuberculosis has also been reported to trigger autoimmunity including multiple sclerosis and type 1 diabetes mellitus (T1DM).

In 2004 Mycobacterium chimaera were identified as having a unique genetic composition of the Mycobacterium avium complex but different from both M. avium and M. intracellulare. Recently contamination of the heater-cooler system during cardiac surgery resulted in some device-related infections due to M. chimaera.

The biochemical reactions with Mycobacterium avium complex are catalase-positive, negative for niacin, nitrate reduction and tween hydrolysis. The biochemical methods are inadequate for clinical use. Currently, molecular techniques have been applied and Mycobacterium avium complex polymerase chain reaction (PCR) multiplex developed, which can detect the individual components of the Mycobacterium avium complex. Restriction fragment length polymorphism (RFLP) and multilocus sequence typing (MLST) are some other ways to identify and diagnose Mycobacterium avium complex infections.[4][5][6]

Epidemiology

Mycobacterium avium complex is ubiquitous and has been reported from the Americas, Asia, and Europe. There are pockets of high prevalence throughout the world. In the United States, the prevalence varies from 1.4 to 6.6 per 100,000 population, but no endemic area has been recognized. Recently a trend towards increasing Mycobacterium avium complex infections has been identified. A seasonal trend in mycobacterial infections around the incidence cycle of 12 months, with peaks in late winter/spring and troughs in autumn, was noted. Women had a higher prevalence, up to 1.6 fold relative to men. A study done in Australia has shown a higher male prevalence (OR 2.1). The differences may be due to the nature of pulmonary involvement. Women have increased predilection for the nodular/bronchiectatic disease also known as Lady Windermere syndrome. Mycobacterium avium complex has been isolated from the environment from the soil, aerosolized water, bathrooms, house dust, birds, farm animals, hot water systems, cigarette components, and house dust. The ecological niche of this organism has not been identified.[7][8]

Pathophysiology

MAC is acquired by inhalation and can also be ingested into the gastrointestinal tract, where it adheres to the mucosal epithelial cells and infects the macrophages. From the submucosal tissues and lymph nodes, the organism is then carried by lymphatics to the rest of the body. In most people, disseminated MAC infection will occur when the CD4 count is less than 50 cell per microliter. In patients who do not have HIV, the most important risk factor for MAC infection is underlying lung disease. MAC has also been associated with bronchiectasis and a hypersensitivity pneumonitis-like reaction.[9]

History and Physical

Mycobacterial infections including Mycobacterium avium complex infections can be categorized into several clinical patterns including pulmonary disease, skin, and soft tissue infections, musculoskeletal infections, disseminated disease, catheter-associated disease, and lymphadenitis. Pulmonary disease is the most common presentation. Mycobacterium avium complex infections occur in both immunocompetent and in immunosuppressed patients. M. avium is the most frequent organism in HIV, and immunosuppressed patients, about 40% of pulmonary infections in immunocompetent patients, can be due to M. intracellulare. With the addition of new members to the Mycobacterium avium complex, the extent of involvement of each organism within the Mycobacterium avium complex is unknown.

Risk factors for Mycobacterium avium complex pulmonary disease are pneumoconiosis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, other chronic lung diseases, persons with thoracic and skeletal abnormalities such as severe scoliosis, straight back syndrome, patients with mitral valve prolapse, CD4 less than 50 in AIDS patients, low CD4 in lymphoreticular malignancies, elderly women who suppress cough, immunosuppression post-transplant and in patients with deficiency in IFN-gamma production as well as IFN-gamma receptor deficiency. Siblings of an index patient have a much higher prevalence of Mycobacterium avium complex infection compared to the general population. There are no known risk factors for cutaneous Mycobacterium avium complex infection and cervical lymphadenitis due to Mycobacterium avium complex.

The Mycobacterium avium complex pulmonary disease can be radiologically classified into fibro-cavitary and nodular bronchiectatic types. Case reports for atypical presentations such as pulmonary nodules, pleurisy, multiple cavitary nodules and pleural effusion with hydropneumothorax have been published. Pleural involvement may be seen in 5% to 15% of patients.

Symptoms in immunocompetent patients are nonspecific, with chronic cough as the most frequent symptom. Fever and hemoptysis are not as frequent as in tuberculosis and uncommon in HIV patients. Fibro-cavitary disease is more common in Caucasian men, occurs in the setting of underlying structural lung disease, presents with worsening cough, hemoptysis and constitutional symptoms.

The bronchiectasis with centrilobular nodules has a predilection for the middle lobe and the lingula. In the fibro-cavitary forms, the cavities are thin-walled with a predilection to the upper lobes. Elsewhere there may be tree-in-bud opacities, suggesting endobronchial spread.

A chest x-ray may not show bronchiectasis very well. A high-resolution CT (HRCT) is more sensitive to changes such as bronchiectasis, small nodules, tree-in-bud appearance, ground-glass opacities, and pleural thickening.  When compared to pulmonary tuberculosis, upper lobe cavitation is less common and middle lobe bronchiectasis more frequent in Mycobacterium avium complex pulmonary infections. HRCT may show a feeding bronchus sign, which suggests that peribronchial nodules due to Mycobacterium avium complex infection evolve into focal cystic bronchiectasis and manifest as cavitary lesions; in this regard, the cavities are different from tuberculosis, where cavities are due to caseous necrosis of lung parenchyma. In the nodular-bronchiectatic form, the nodules are smaller than 5 mm to 10 mm and closely associated with areas of bronchiectasis. Both radiologic forms of Mycobacterium avium complex pulmonary infections are prevalent equally, but the nodular bronchiectatic form is more common in elderly Caucasian women, who suppress a cough while the fibro-cavitary disease is more common in white men with underlying chronic lung disease.

Mycobacterium avium complex is also the most frequent nontuberculosis mycobacterial species cause of cervical lymphadenitis commonly seen in children.

Hypersensitivity pneumonitis-like presentation can occur. Initially thought to be an allergic reaction only, the current opinion may be shifting towards both infection and inflammation. 

Disseminated infections with Mycobacterium avium complex occur in the setting of AIDS and immunosuppression.

Evaluation

Infection with Mycobacterium avium complex may be asymptomatic. Colonization of the pulmonary tract without infection is unproven in the nontuberculosis mycobacterial species diseases. Contamination of a sputum sample is possible therefore more than one sputum sample is required. Symptoms are non-specific, and the differential diagnosis is wide, microbiologic isolation is required to make the diagnosis. As per recommendations of the Infectious Disease Society of America (IDSA), a minimum evaluation of a patient suspected of nontuberculous mycobacterial infection should include a radiologic, microbiologic and clinical evaluation. Clinically exclusion of pulmonary tuberculosis is important. Clinical evaluation of underlying diseases, risk factors for mycobacterial diseases, and the ability to tolerate prolonged multidrug therapy should be undertaken.

While the Mycobacterium avium complex is not a part of the microbiome of the lung, there is no need to treat all patients with sputum positive for Mycobacterium avium complex. Selecting patients for therapy is a clinical calculus combining, microbiologic, radiologic and clinical criteria. The therapy is long, and there is significant potential for adverse drug reactions.[10][11]

Treatment / Management

The macrolide antibiotic is the backbone of therapy for Mycobacterium avium complex infections. The Infectious Disease Society of America recommended triple antibiotic therapy for fibro cavitary and severe nodular bronchiectatic disease. For moderate to mild disease, dual antibiotic therapy is sufficient. Observation is reasonable but in general Mycobacterium avium complex pulmonary infections are progressive, and eventually, a patient will have indications for therapy. In this situation, expert opinion suggests, that sputum should be checked once in three months and radiological evaluation once in six months. A chest x-ray may be sufficient for the fibro-cavitary disease, but HRCT is needed to assess nodular bronchiectatic disease. Risk factors for progressive disease are cavitary disease, low body mass index, older age, and co-morbidities. The risk of progression must be weighed against the potential risk of treatment.[12][13][14]

The medications used in the treatment of Mycobacterium avium complex infections are a macrolide, clofazimine, rifampin, rifabutin, ethambutol, fluoroquinolone, linezolid, and aminoglycosides. There is no proven correlation between in-vitro susceptibility and clinical response. The only susceptibility to macrolide and amikacin may be useful clinically. If the patient is intolerant to first-line drugs than susceptibility testing to secondary medications may be of some value. The goal of therapy is to have culture negativity for 12 months. Sputum conversion takes three to six months. Close monitoring for drug intolerance is required. At the initiation of therapy, baseline audiogram, electrocardiogram, an eye exam for visual acuity and color discrimination complete blood count and the comprehensive metabolic panel must be obtained.

For severe and fibrocavitary disease, a typical three-drug regimen consists of daily oral azithromycin, rifampin, and ethambutol; intermittent dosing is inadequate in this situation. For severe fibrocavitary disease, parenteral aminoglycoside can be used in the initial phase (first eight to 16 weeks of therapy) as a fourth agent, but there is no proven benefit. In patients who cannot tolerate parenteral aminoglycoside, inhaled amikacin can be used. For severe localized cavitary disease, surgical resection, after the sputum becomes negative, can be considered. Surgery is not without risk of formation of a bronchopleural fistula. For mild to moderate nodular bronchiectatic disease intermittent dosing of the three-drug regimen can be used.

No prospective studies evaluate the efficacy of the macrolide-containing three-drug or two-drug regimens. However long term sputum conversion rates of 86% have been documented. Small randomized controlled trials comparing three-drug and two-drug regimens showed higher treatment failure with two-drug therapy. Macrolide containing regime was not evaluated in this trial.

The key to successful therapy is close monitoring for disease worsening and drug-related toxicity. Patients should be followed once every two months while on therapy. Introduce one drug at a time and a lower dose and increase to a therapeutic dose over two to five days. Therapeutic drug monitoring is of no proven value. Azithromycin peak levels can be measured in the setting of malabsorption or treatment failure or if the dose is considered to be low. A peak level of greater than 0.4 mcg/mL was independently associated with the favorable microbiologic response. Rifampin can decrease macrolide levels. A study by Koh WJ et al. in 101 patients showed no correlation between clarithromycin level and favorable microbiologic response.

Differential Diagnosis

• HIV
• Lymphoma
• Fungal infections
• Hypersensitivity pneumonitis
• Sarcoidosis
• Tuberculosis

Complications

• Severe wasting
• Hepatomegaly
• Splenomegaly
• Generalized lymphadenitis
• Synovitis, tenosynovitis

Pearls and Other Issues

Mycobacterium avium complex in HIV patients

Mycobacterium avium complex infections occur when the CD4 counts are less than 50. Mycobacterium avium complex infections frequently present as disseminated infections. Disseminated Mycobacterium avium complex infections are uncommon outside of HIV patients. Most infections are due to M. avium. For unknown reasons, M. intracellulare does not cause disseminated disease in HIV patients. The clinical presentation of the disseminated disease is non-specific. Common clinical findings are fever (more than 80%), night sweats (more than 35%), weight loss (more than 25%), abdomen pain, diarrhea, mesenteric lymphadenopathy, anemia, elevated alkaline phosphatase, and elevated lactate dehydrogenase.

Antiretroviral therapy can begin simultaneously. Rifabutin can be used instead of rifampin to avoid drug-drug interactions with antiretroviral agents. Preferred regimens must contain clarithromycin and ethambutol.

Mycobacterium avium complex in Cystic fibrosis patients

The principles of the therapy are the same as in an immunocompetent patient. There may be some patients who may tolerate medications but never become sputum negative, in which case prolonged treatment may be required. Azithromycin is preferred over clarithromycin due to a better tolerance profile.

Mycobacterium avium complex in transplant patients

Nontuberculosis Mycobacterial species infections are more common in hematopoietic stem cell transplant patients than in solid organ transplant patients. The most common site of infection has been the lungs, and there is an increasing trend. Most infections have been in the setting of chronic rejection.

Enhancing Healthcare Team Outcomes

MAC is a lung pathogen and most commonly affects patients with HIV and those who are immunosuppressed or have malignancies, and is best managed through an interprofessional team approach. The organism typically infects the lung but can affect any other organ in the body at the same time. Besides the infectious disease expert, the nurse and pharmacist need to educate the patient on the importance of drug compliance and the potential adverse effects of therapy. In addition, these patients develop severe wasting and a dietary consult is recommended to ensure that they consume at least 1800 to 2000 calories a day. Patients with MAC need to be educated on the symptoms of anemia and when to seek help. Many require repeated transfusions and hence, an outpatient nurse should follow up on these patients. Since many patients with MAC have low exercise tolerance, a physical therapy program is recommended to increase muscle mass and improve exercise endurance. The pharmacist should educate the patient on compliance with HAART, or the macrolide therapy may not be as effective. Nursing will play a significant part in monitoring treatment effectiveness, as well as being alert for signs of adverse drug events, and inform the clinician team promptly. Finally, patients with MAC need regular X-rays to monitor their disease progression and hence follow up visit with a pulmonologist is recommended.[15][16] These types of interprofessional cooperative efforts will drive better patient outcomes. [Level V]

Evidence-based Outcomes

Before the availability of the macrolide antibiotics, the majority of patients who acquired MAC died within 3 to 4 months. By the 1990s, the survival improved to 9 to 12 months. Today, with the availability of HAART and macrolides, many people have a much-improved outcome. However, despite treatment, wasting is common and many patients develop anemia requiring multiple transfusions. In patients without HIV, the course of MAC is somewhat mild with a life expectancy of 50% at 5 years. In patients with HIV, 5-year survival rates of 20 to 70% are reported- this depends on compliance with HAART therapy. Even patients with extensive disease can recover with treatment, but relapse is common. In children, MAC tends to cause lymphadenitis which runs a benign course. Sometimes lymph node rupture and sinus tracts may develop.[3][17] (Level V)