By Karim Al-Itani and Yasamin Nassimi
The Mycobacterium avium complex (MAC) is amongst the most frequent species involved in the Nontuberculous mycobacteria (NTM); this complex is primarily composed of M.avium and Mycobacterium intracellulare. M.avium, is a slow-growing gram positive bacteria that is commonly found in soil and water sources. This intracellular pathogen has the ability to resist the immune mechanisms of the host, and the respiratory tract is amongst the most susceptible sites of infection. In addition to the infections within the respiratory tract, M.avium can also invade the bones, joints, lymph nodes and spread systemically. Infection acquisition may occur through ingestion, inhalation and dermal contact with environmental sources or medical devices.
M.avium is an opportunistic pathogen, meaning it can cause disease when the host’s immune system is impaired (e.g. HIV). Acquisition of M.avium results in the adhesion of the microorganism to the mucosal epithelial cells in the intestinal lining and infection of the macrophages. Upon the invasion of the submucosal tissue and lymph nodes, the bacterium will be carried to the rest of the body via the lymphatics. In most individuals, the spread of the infection will occur when the CD4 count is less than 50 cells/mL. The presence of CD4 cells is crucial in achieving an effective immune response to pathogens. Thus, a low CD4 count renders the host susceptible to infections by opportunistic pathogens. Additionally, another risk factor for MAC infections includes the presence of underlying lung diseases.
There are two major phenotypes associated with MAC pulmonary diseases (MAC-PD): fibrocavitary and nodular bronchiectatic (NB). The fibrocavitary form is characterized by the presence of lesions in the upper lobes of the lung, and occurs predominantly in older males with underlying lung diseases, such as previous pulmonary tuberculosis and chronic obstructive pulmonary disease (COPD). The NB form often develps in postmenopausal women and can cause multiple nodules in the right middle lobe and left upper lobe of the lung.
Symptoms in patients with competent immune systems are nonspecific, with chronic cough being the most common symptom.
Figure 1: Image of M.avium pulmonary disease of the NB form in a 47 year old Woman. Chest radiograph shows small nodular clusters in both lower lung zones. HRCT shows small centrilobular nodules in the right middle lobe and the left upper lobe. Source: Jae Seuk Park, 2009.
Currently, MAC species, especially M.avium, are mainly responsible for the majority of pulmonary infections caused by NTM. A Japanese study found that the incidence of MAC infections increased from 5.2/100,000 in 2007 to 13.1/100,000 in 2014; with the pulmonary diseases caused by M.avium having the highest prevalence in the north and east of Japan.
Comparably, in Europe, M.avium was the most frequent MAC species among pulmonary and extrapulmonary samples; as observed in studies done in Portugal (58.0%), Denmark (50.7%) and Italy (41.5%).
The same overall pattern of MAC pulmonary and extrapulmonary diseases has been found in the United States of America, with M.avium being the most frequent isolate among MAC species (54.0%).
A potential explanation for the elevated prevalence of MAC and M.avium infections could be linked to the improvement of laboratory screening methods and increased awareness towards these infections in clinical settings.
M. avium bacteria are characterized by the presence of a hydrophobic cell wall and by their mycolic acid constituents composing their core. Mycolic acids are densely packed with a variety of GPLs, which are a class of glycolipids. The presence of GPLs is responsible for the immunomodulatory properties of M. avium that makes it a successful pathogen.
First of all, the GPL component of the bacterium prevents the formation of the phagosome-lysosome complex. A phagosome is a cytoplasmic structure that exists inside specialized immune cells known as phagocytes; later, the fusion of the phagosome with the lysosome results in a phagolysosome complex. Formation of the phagolysosome complex is crucial for the destruction of intracellular microorganisms. The ability of GPLs to support the survival of mycobacteria in phagocytes is due to the interaction between the GPLs with mannose receptors on the surface of the phagocytes. Moreover, the accumulation of GPLs inside macrophages leads to an amplified proinflammatory response through interactions with Toll-like receptors. This phenomenon is essential as it leads to amplified infection impacts, without the necessary presence of the microorganism.
Lastly, the synthesis of GPLs is required for the adhesion and secretion of biofilms. It has been suggested that inactivation of genes responsible for the synthesis of GPLs, leads to the impairment of the microorganism to slide or stick to surfaces. Moreover, biofilm formation contributes to the adaptation of virulent strains to environmental anoxia and nutrient limitations, by lowering the metabolic rate and reducing the rate of cell division.
Figure 2: Electron microscopy images of human macrophages infected with M.avium serotype 4 strain (A) or M.avium serotype 2 strain (B) for 5 days. Black arrows indicate the individual bacteria within each vacuole. Source: Birkness et al., 1999.
Diagnosis with MAC-PD has varying treatment plans which is determined by disease progression. In nearly half of the patients, untreated MAC-PD does not progress for several years after diagnosis and negative culture conversions (no bacteria detected by testing) are recorded. So, it is important to consider what risk factors patients have prior to the initiation of treatments to avoid unnecessary medical expenses and adverse drug reactions. Some risk factors include cavitary lesions, low BMI, poor nutritional status, and extensive disease symptoms. In cases where treatment is warranted, a three-drug combination of macrolide-based antibiotics is used. Standard treatment uses three doses per week with increased administrations in severe cases.
This approach has been associated with better patient outcomes. However, this was only recorded in 32-65% of patients based on 5 systematic reviews. On top of its limited success, this treatment plan is limited by macrolide-resistant MAC strains which do not have any effective medication options. In cases where drug treatment fails, lung resection surgery is considered. This has led to successful culture conversion rates between 80-100%. However, the surgical approach is associated with postoperative morbidity and mortality in 0 to 50% of cases. This number can be significantly lowered through improved patient selection, preoperative assessments, surgical techniques and postoperative measures.
Finally, alternative therapeutic agents are being tested for macrolide-resistant MAC-PD. Clofazimine led to culture conversions in 87% and 99%. of patients in two studies conducted. However, adverse reactions have been recorded in roughly 50% of patients. Overall, the current treatment for MAC-PD is subpar and novel treatment approaches should be developed for patients with poor prognoses.
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