Lung diseases often remain hidden until advanced stages because their early symptoms tend to be subtle and easily overlooked. These conditions can arise from lifestyle choices, environmental exposures, or be secondary to chronic illnesses like diabetes. Among infectious causes, a challenging group of bacteria known as mycobacteria can invade the lungs and trigger severe disease.

Mycobacteria are complex organisms categorised mainly into tuberculosis-causing and non-tuberculous species. The latter group includes the Mycobacterium avium complex (MAC), which is particularly problematic in immunocompromised individuals. This article focuses on the complications of MAC lung disease in patients with weakened immune systems.

Understanding MAC lung disease

Mycobacterium avium complex (MAC) lung disease is a chronic lung infection caused by a group of slow-growing, ubiquitous, and non-tuberculous mycobacteria (NTM). Among the NTM, the most common bacteria that cause disease in humans belong to the Mycobacterium avium complex (MAC). This complex consists of Mycobacterium avium, Mycobacterium chimaera, and Mycobacterium intracellulare.¹ M. avium and M. chimaera are isolated from both natural and treated water sources, whereas M. intracellulare is mostly found in soil.² These organisms have lipid-rich outer membranes, making them relatively resistant to chemical disinfection, such as chlorination.

According to the American Journal of Respiratory and Critical Care Medicine, MAC lung disease (MAC-LD) is classified into two types: fibrocavitary disease and nodular bronchiectatic disease. Fibrocavitary disease is more severe and often occurs in individuals with a history of smoking or chronic lung disease like COPD. Nodular bronchiectatic disease usually affects non-smoking middle-aged women.⁵

MAC causes three major disease presentations: pulmonary disease, which can affect immunocompetent individuals; disseminated MAC infection, primarily seen in immunocompromised patients; and cervical lymphadenitis, which also occurs in healthy hosts.³ MAC can also lead to conditions such as septic arthritis and tenosynovitis.³ Although MAC lung disease is not contagious between humans, its incidence and prevalence are rising globally. This increase corresponds with the decline of tuberculosis worldwide.⁴ Factors contributing to this rise include ageing populations, chronic lung disease history, more immunocompromised individuals, and reduced cross-immunity with M. tuberculosis.⁵

Risk factors for MAC lung disease in immunocompromised patients

In immunocompromised individuals, several host-related factors can significantly elevate the risk of MAC colonisation and subsequent lung infection. These include:

• Active malignancies, particularly those involving the lungs
• Pre-existing pulmonary conditions such as chronic obstructive pulmonary disease (COPD) and bronchiectasis⁶
• Occupational lung diseases, such as pneumoconiosis
• Congenital or acquired thoracic and skeletal abnormalities⁶
• Mitral valve prolapse, which may alter pulmonary circulation and host defences
• Post-organ transplant status requiring long-term immunosuppressive therapy⁶

While MAC infection does not favour any particular racial group, Mycobacterium intracellulare appears to be more pathogenic and is frequently associated with postmenopausal women.⁶ The predominant route of infection is through the inhalation of environmental aerosols contaminated with MAC organisms.

Notably, even in otherwise healthy individuals, exposure to inadequately maintained and poorly disinfected hot tubs has been linked to a condition known as hot tub lung. This presents with diffuse pulmonary infiltrates and granulomatous inflammation. MAC organisms are often isolated from both the hot tub water and the patient’s lung tissue in such cases.⁹

Major complications of MAC lung disease in immunocompromised patients 

 The most common bacterium that causes pulmonary diseases in MAC is Mycobacterium intracellulare, while Mycobacterium avium mostly causes extrapulmonary diseases, accounting for 38.9% and 25.0% infections, respectively.¹ These two bacterial species cause approximately 61% of NTM infections in people. The major complications that can occur in immunocompromised patients with MAC lung disease include;

• Disseminated MAC Infections (DMAC): MAC can cause disseminated disease, which starts from infecting the mucosal surfaces such as the lungs and intestines. This is followed by multiplication and invasion into other organs and tissues of the body through the bloodstream. The most commonly observed clinical symptoms of disseminated MAC infection include persistent fever, night sweats, weight loss, fatigue, lethargy, and loss of appetite.⁷ Disseminated MAC infections can cause skull defects such as scalp abscess, which can cause skull destruction and brain infection as it progresses. ⁸ Patients with AIDS who are not on antiretroviral therapy usually develop DMAC and are associated with a shorter life span compared to AIDS patients who do not suffer from DMAC⁵
• Pulmonary Complications: Some prominent respiratory complications associated with MAC lung disease include: chronic cough,   weakness, hemoptysis, weight loss, and low-grade fever. In severe cases, MAC lung disease can lead to respiratory failure and can cause or exacerbate bronchiectasis, a condition where the airways become widened and scarred. ¹ There could also be the formation of cavities in the lungs, particularly in the fibro-cavitary form of MAC lung disease. This can lead to hemoptysis and other complications. If left untreated, MAC lung disease can further cause lung damage and worsening respiratory symptoms
• Systemic Complications: MAC infection can get to the liver, which responds by forming granulomas, which are clusters of immune cells, primarily macrophages, that attempt to contain the bacteria. These granulomas can build up in the liver tissue, contributing to its hepatomegaly.¹⁰ This can also occur in the spleen and cause splenomegaly
• Generalized lymphadenitis, synovitis, tenosynovitis: Lymphadenitis, which is the inflammation and enlargement of the lymph nodes, can be a complication of MAC lung disease. Generally, MAC lymphadenitis affects the anterior cervical lymph nodes unilaterally and occurs primarily in children between the ages of 1 and 4 years.⁵ It also tends to occur more often in the winter than in other seasons.¹¹ Additionally, MAC lung disease can lead to synovitis and tenosynovitis in various ways. These include: hematogenous spread, local extension involving the joints and tendon sheaths, and prompting due to a weakened immunity, which makes the patient more vulnerable to bacterial invasion beyond the lungs¹²
• Drug-induced Complications: Long-term administration of medication for the treatment of MAC-LD is also associated with gastrointestinal and ocular complications. These include: hepatotoxicity, leucocytopenia, thrombocytopenia, cutaneous reactions, ocular toxicity, and increased serum creatinine. The risk factors for these drug-induced hepatotoxicities include older age, sex, history of HBV/HCV infection, HIV co-infection, underlying liver injury, high alcohol intake, and poor nutrition¹³

Why are immunocompromised patients more at risk of developing these complications? 

Patients with a weakened immunity are typically unable to fight off various organisms and prevent the invasion and dissemination of MAC in their bodies. Other reasons for increased susceptibility to MAC lung disease include the following; 

• Increased risk of opportunistic co-infections 
• Immunosuppressive health conditions such as HIV, organ transplant 
• Exposure to environmental toxins 
• Certain medications, such as corticosteroids, which further suppress the immune system and ease the entry of other pathogens
• Patients with a history of smoking and pectus excavatum¹⁴

Management of MAC lung disease in immunocompromised patients

According to the British Thoracic Society (BTS) guideline for the management of MAC-LD, initiation of antibiotics is considered for patients experiencing severe symptoms of the disease and disease progression. Thus, for patients who have MAC-LD with minimal symptoms, non-severe radiographic changes, and low bacterial load, a recommended strategy is to start with the treatment of symptoms and then continue clinical observation with subsequent hospital visits. To improve pulmonary health, people with MAC-LD are subjected to non-pharmacological management, which includes chest percussion and draining secretions and mucus from the airways and lungs (i.e, postural drainage) as well as use of mucolytic agents. ¹⁵  

The following are indicators for the initiation of treatment of MAC-LD, as well as individual assessment of the benefits and risks associated with treatment;

Treatment of MAC lung disease

People with MAC-LD are treated based on the severity of the disease and the resistance of the causative organism to various antibiotics. According to the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines, the standard three-drug combination regimen for MAC-LD is macrolide (azithromycin), rifamycin (rifampicin), and ethambutol. This three-drug therapy should be given for at least 12 months after negative test results from sputum culture are seen. Parenteral drugs, such as streptomycin or amikacin, can be added to strengthen the regimen, particularly for patients with a severe form of MAC-LD accompanied by complications.¹⁷

The dosing frequency for the treatment regimen differs as well. Three times per week administration is recommended for patients with non-cavitary nodular bronchiectatic disease. Conversely, daily treatment is advised for people with MAC-PD with cavities.¹⁷ Intermittent therapy can decrease the adverse effects of drugs. Additionally, the regimen for unmanageable and chronic MAC-PD entails the use of four drugs: macrolide, rifamycin, ethambutol, and amikacin inhalation suspension.¹⁷

FAQs

Can MAC-LD be prevented?

Although MAC bacteria are ubiquitous, completely avoiding them could be a challenge. However, to reduce the risk of developing MAC lung disease in immunocompromised patients, it is essential to include preventive medications and careful monitoring of CD4 counts, and reduce exposure to environmental toxins and hot tubs.

How is MAC-LD diagnosed in immunocompromised patients? 

Various tests can be used to diagnose this disease. These include chest X-rays and CT scans to detect changes in the lungs associated with MAC-LD. Sputum cultures can also be collected to examine the growth of MAC. However, since the isolation of MAC is usually not enough to diagnose MAC-LD, the ATS and IDSA published criteria for the diagnosis of non-tuberculous bacterial lung disease.¹⁸ 

Summary

• Mycobacterium avium complex lung disease (MAC-LD) is a debilitating and insidious lung disease caused by non-tuberculous bacteria
• There are two major types of MAC-LD: nodular bronchiectasis, whereby the infection develops in the small airways and resembles lung nodules upon imaging. The second type is fibrocavitary, which is a more severe form of MAC-LD. It causes a hole in the lung tissue and is more common in people who smoke
• The major risk factor for developing MAC-LD is a history of lung disease. Other risk factors include: people with skeletal or thoracic abnormalities, people with COPD, etc
• MAC-LD can cause complications in immunocompromised patients, such as disseminated MAC infections, pulmonary and systemic complications, etc
• Treatment of MAC-LD depends on the severity of the disease and the response of the patient to previous therapies
• Chest percussion, postural drainage, and use of mucolytic agents are some of the non-pharmacological methods of managing MAC-LD
• Certain guidelines have prompted the development of a three-drug therapy for the treatment of MAC-LD in addition to the use of parenteral drugs