Atypical Mycobacterial Disease

Etiology

One defining feature of most atypical mycobacteria is that they are acid-fast bacilli. This staining property detected via the Kinyoun method is due to its hydrophobic mycolic acid outer layer. This mycolic acid layer allows them to form thick biofilms, enabling their survival in harsh environments that are not as well tolerated by other bacteria. These biofilms stunt the ability of antibiotics to penetrate bacteria effectively. They allow for survival in varying temperatures and protect the bacteria from being killed by water-purifying chemicals such as chlorine, disinfectants, and cleaning products. Biofilms also allow the bacteria to survive in oxygen-rich and anaerobic environments. Another defining characteristic of mycobacteria is their slow rate of growth. Atypical mycobacteria are divided into rapid and slow-growing categories. Rapid-growing organisms take 7 to 30 days to grow on culture. Slow-growing organisms take several weeks to months to demonstrate growth. The type of disease caused by these organisms depends on the mode of inoculation and the host's susceptibility to infection. Pulmonary infection occurs via inhalation of aerosolized material containing the bacteria. In contrast, lymphadenitis is often caused by ingestion or penetration through the soft tissues, and skin and soft tissue infection by access through skin breakdown or by indwelling medical equipment.[1][2]

Epidemiology

Atypical mycobacteria are found in both natural and human-made environments. In nature, they are found in the highest concentrations in the soil and water. Geographically, they have higher concentrations in pine forests and the swamp-like regions of the southern United States. They also inhabit plumbing and human-made water sources with higher concentrations in urban areas. They are resistant to water treatment chemicals and can be found in drinking water, showers, hot tubs, and saunas. Estimates of the rate of pulmonary disease are between 5 to 10 per 100,000 per year. Various studies have estimated the rate of all causes of atypical mycobacterial infection in children to be between 0.6 and 3.3 per 100,000. Estimates of the rate of all causes of infection in adults are between 20 to 47 per 100,000.

MAC/MAI pulmonary disease is most commonly found in adults and those with impaired host defense of the lung, such as Human immunodeficiency virus (HIV), patients on TNF-alpha inhibitors, and cystic fibrosis. Adult pulmonary disease preferentially impacts White, middle-aged, or older men, who often have comorbid diagnoses of chronic obstructive pulmonary disease, alcohol use, or tobacco use. A less common presentation referred to as "hot tub lung" can be seen as part of a hypersensitivity syndrome related to bathing or recreational water exposure following MAC exposure. Disseminated MAC/MAI is primarily observed in patients with significantly immunocompromised states, such as acquired immunodeficiency syndrome.[3][4][5][6]

Pathophysiology

When encountered by the immune system, atypical mycobacteria are taken up by macrophages, causing the macrophages to release IL-12 and TNF-alpha. IL-12 release activates the IL-12-interferon gamma pathway. This pathway further recruits additional macrophages, neutrophils, and T-cells. This process ultimately results in the killing of these intracellular bacteria by nitric oxide and free radicals. The macrophages, neutrophils, and T-cells recruited to the site of infection can sometimes result in granuloma formation, creating a fibrinous mass walling off the infection and isolating it from the rest of the body. Atypical mycobacteria can often evade this response due to the ability of the glycoproteins in their cell wall to inactivate the phagosome-lysosome fusion process and free radical destruction, allowing the bacteria to live as intracellular organisms within macrophages.

Lymphadenitis: According to the American Thoracic Society and Infectious Disease Society of America, Mycobacterium avium complex bacteria cause approximately 80% of atypical mycobacterial infections in children. The progression of atypical mycobacterial lymphadenitis has been described in 4 stages by Toretta et al (2018). The first stage describes a unilateral submandibular, preauricular, or cervical chain lymph node that slowly and painlessly enlarges over several days to months. The author noted stage 1 to be unlikely to show systemic symptoms. Stage 2 describes the presence of tenderness indicative of necrosis within the lymph node. Stage 3 describes erythematous discoloration of the overlying skin. Stage 4 describes the progression of skin breakdown to the formation of sinus tracts.

Pulmonary: The 3 species that comprise the vast majority of atypical mycobacterial pulmonary infections are the Mycobacterium avium complex bacteria (approximately 80%), Mycobacterium kansasii, and Mycobacterium abscessus. Mycobacterium avium complex infections can be further grouped into 2 different presentations. The first presentation is found more commonly in middle-aged males with the risk factors of long-term alcohol and tobacco abuse. In these patients, the MAC bacteria tend to form large fibrocavitary lesions in the apex of the lung. These lesions can rapidly progress to encompass significant areas of the lung within 1 to 2 years and generally result in morbidity and mortality at a much faster rate. The second type of presentation of MAC lung disease more commonly affects postmenopausal caucasian women. In this presentation, the bacteria form small pulmonary nodules and cylindrical bronchiectasis with a concentration of nodules in the right middle lobe and ligula of the left upper lobe of the lungs. Similar presentations to MAC pulmonary disease are seen with Mycobacterium kansasii and abscessus. Mycobacterium kansasii tends to form large fibrocavities in the apex of the lung, similar to the first type of MAC disease presentation. A much smaller proportion of infections resemble the nodular and bronchiectatic type of presentation. Mycobacterium abscessus infection usually presents with a nodular and bronchiectatic presentation concentrated in the upper lung fields. Mycobacterium abscessus forms fibrocavities in approximately 15 percent of infections. 

Skin and Soft Tissue: Atypical Mycobacteria enter the skin and soft tissue through trauma, surgical procedures, or indwelling medical equipment. All species of atypical mycobacteria can cause skin and soft tissue infections. The most common species that cause skin and soft tissue infection are Mycobacterium chelonae, abscessus, fortuitum, ulcerans, and marinum. Mycobacterium marinum infection is also known as the fish tank granuloma after originally being discovered to cause soft tissue infection in fish tank workers/enthusiasts. It most commonly causes localized erythema and granuloma formation of the digits, which can progress to nodular lymphangitis of the hands and forearms similar in appearance to sporotrichosis. These bacteria more rarely can affect tendons and joint spaces and cause osteomyelitis. Immunocompromised patients have had recorded cases of disseminated infection.

Mycobacterium ulcerans is also known as the Buruli ulcer. These ulcers are known for their large areas of skin involvement, deep ulceration, and marked cosmetic disfigurement. They most commonly begin as a small, painless nodule, which slowly begins to ulcerate. Poorly defined and irregular borders characterize these ulcers and can cover extensive sections of the body. Other variations of these lesions may also begin as localized erythema, subcutaneous edema, or a violaceous skin rash. Of note, approximately 15% of Mycobacterium ulcerans infections cause osteomyelitis. Mycobacterium fortuitum most commonly presents as a solitary subcutaneous nodule. Most cases of Mycobacterium fortuitum infection have low morbidity and limited infection. Immunocompromised patients, however, have been known to suffer from the more serious and disseminated infection. Mycobacterium abscessus most commonly forms an abscess under the site of skin trauma/penetration. These abscesses are painful to the touch, may form draining sinus tracts, and may progress to ascending lymphadenitis. Disseminated disease can occur in immunocompromised individuals and produce diffuse subcutaneous nodules with lymphadenitis. Mycobacterium chelonae presents in most cases as small disseminated cutaneous nodules that are painful to the touch. The skin surrounding these lesions is often hyperpigmented. Lesions may also drain, form sinus tracts, and appear as cellulitis or non-healing ulcers. Infection is most common in immunocompromised patients. Mycobacterium chelonae has also been known to cause osteomyelitis.[1][7][8][9]

Histopathology

Atypical mycobacteria contain a hydrophobic mycolic acid layer in their cell wall. Due to this property, they are not typically seen using Gram staining. The best method for detecting atypical mycobacteria is fluorochrome staining, a type of acid-fast staining where these bacteria appear as yellow to orange bacilli. Notably, rapidly growing mycobacteria are frequently not seen even with fluorochrome staining, and atypical mycobacteria overall are visualized in only 30% to 60% of cases. Rapidly growing mycobacteria are noted to be more sensitive to the decolorization process in acid-fast staining. It is thought that using more delicate methods for decolorization can increase the chance of visualizing these bacteria. Other less sensitive staining methods, including the Ziehl-Neelsen and the Kinyoun stain, may also be used.[1]

History and Physical

Lymphadenitis

Most mycobacterial lymphadenitis cases are present in children under 5 whose parents have noticed 1 or more soft but firm, unilateral, subcutaneous masses, usually in the submandibular or cervical chain regions. The masses are usually non-tender at the beginning of the disease, followed by the later development of fluctuance and even purulent discharge from fistulizing tracts. A diagnosis of mycobacterial lymphadenitis is frequently suspected after enlarged cervical nodes in children fail to respond to empiric antibiotic therapy directed at Staphylococcus and Streptococcus or fail to resolve under watchful waiting for a presumed viral process.

Skin and Soft Tissue Infections

Mycobacterial skin and soft tissue infections can result from localized or disseminated infection and occur in patients of all ages. Patients with localized lesions may give a history in which they experienced trauma to their skin while swimming (freshwater, saltwater, swimming pool, hot tubs). Other risk factors for skin and soft tissue infections include patients who are currently immunosuppressed or have had recent surgical procedures. Skin lesions can range from erythematous papules/nodules that progressively ulcerate to ecthyma, resembling cellulitis. A separate category of skin lesion, the Buruli ulcer, is characteristic of a painless area of soft tissue swelling that slowly begins to ulcerate with poorly defined and irregular borders. Untreated, they can grow from a few centimeters to span large areas of the body. Patients with these lesions are usually from West Africa, Central and South America, Australia, and Japan.

Pulmonary Infections

Mycobacterial pulmonary infection typically presents in patients with impaired host defense of the lung. This includes patients with cystic fibrosis, chronic obstructive pulmonary disease, HIV, and other immunodeficiency syndromes. In patients without known immunodeficiency syndromes, patients are more often male, middle-aged, or older and have a history of comorbid alcohol or tobacco abuse. These patients present with cough and worsening respiratory function in all cases but can also present with pneumonia, hemoptysis, persistent fever, and weight loss. These patients tend to have a much more rapidly progressing disease. Another subset of patients with a more slowly progressing disease and similar symptoms has been identified as women who have undergone menopause and have a lower BMI, scoliosis, or rib cage abnormalities.[1][2]

Evaluation

Mycobacteria can be difficult to detect by laboratory testing. The initial workup for most infections begins with a CBC, which can show a normal to elevated white blood cell count. Inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate can also be normal or elevated. Samples from fluid cultures obtained from soft tissue lesions or excised lymph nodes should undergo acid-fast or fluorochrome staining. Organisms are visualized in around 30% to 60% of cases. Culture of fluid and tissue samples should be obtained and yield an organism in approximately 65% of cases. 90% of patients diagnosed with a disseminated infection have positive blood cultures. Unlike the growth of common bacteria on culture, rapidly growing mycobacteria takes approximately 1 week or more, and slow-growing mycobacteria take several weeks to months to show growth.

Polymerase chain reaction is frequently used on samples to obtain faster results and is more sensitive in diagnosis, yielding an organism around 91% of the time. Tuberculin skin testing can also be used as a nonspecific method to confirm suspected atypical mycobacterial infection. This results in a greater than 10 mm area of induration between 30% and 60% of the time. Diagnosis of pulmonary infection is based on clinical suspicion of an active infection given active pulmonary symptoms, chest X-ray or CT findings, and growth on 2 or more sputum cultures (also accepted as tissue biopsy or lavage cultures).[1][2]

Treatment / Management

Pulmonary

Recommended treatment for adults and children with MAC infections includes azithromycin, rifampin, and ethambutol. Additional drug options are available for each drug class. Three times per week dosing is used in adult nodular/bronchiectatic disease with recommended regimens of azithromycin 500 to 600 mg, or clarithromycin 1000 mg, plus ethambutol 25 mg/kg, plus rifampin 600 mg. Daily dosing is required in cavitary disease with the additional option of 3 times weekly streptomycin or amikacin. Recommended daily dosages are clarithromycin 500 to 1000 mg, azithromycin 250 to 300 mg, and rifampin 450 to 600 mg, with either amikacin or streptomycin. The American Thoracic Society and Infectious Disease Society of America cite a study that suggests tolerable dosages of 25 mg/kg 3 times weekly for both drugs. They also state that certain experts recommend decreasing dosages to 8 to 10 mg/kg (maximum 500 mg) for patients older than 50 years or receiving treatment longer than 6 months. Antibiotics are continued until the patient has had 12 months of negative sputum cultures. The typical time to the first negative sputum culture is 3 to 6 months, with most patients obtaining negative sputum cultures within 12 months. Treatment failure is defined as the lack of sputum conversion after 12 months or the lack of sputum conversion within 6 months without any clinical or imaging improvement. In cases of progressively worsening respiratory status where patients continue to fail sputum conversion, surgical resection of the lung parenchyma containing the cavitary disease may be required.[1][2]

Mycobacterium intracellulare has demonstrated rising minimum inhibitory concentrations and increased resistance to anti-mycobacterial agents compared to Mycobacterium avium, making it more complicated to treat. Alternative agents to treat MAC/MAI pulmonary disease include inhaled amikacin, clofazimine (as a substitute for rifampin), and moxifloxacin. Several other atypical mycobacterial species have been shown to cause pulmonary disease and are generally susceptible to macrolides, rifampin/rifabutin, streptomycin, amikacin, doxycycline, and fluoroquinolones. Notably, pulmonary disease caused by Mycobacterium abscessus is resistant to most antibiotics and can only be cured in a minority of patients by surgical resection. Those who are not cured are administered chronic intermittent antibiotic therapy to attempt to slow disease progression.[1][10]

Lymphadenitis

Treatment for lymphadenitis is based on a 2-drug regimen of 1 macrolide, azithromycin, or clarithromycin, combined with rifampin or ethambutol. Antibiotics are dosed daily and taken until the symptoms are resolved. Surgical resection of infected lymph nodes and tissue is typically used with antibiotic therapy with significantly increased cure rates. The initial antibiotic regimen may be adjusted based on culture susceptibility results.[2] 

Skin and Soft Tissue

Skin and soft tissue infections are treated with combination antibiotic therapy with various options available, including macrolides, doxycycline, fluoroquinolones, trimethoprim/sulfamethoxazole, cephalosporins, or linezolid. Empiric therapies are adjusted once susceptibility testing yields results; however, combination antibiotic therapy is continued due to inducible antibiotic resistance. Surgical debridement is required for infections that are extensive and associated with necrosis.[1]

Differential Diagnosis

Lymphadenitis

• Tuberculosis
• Viral lymphadenitis
• Leukemia/lymphoma
• Staphylococcus aureus or other bacterial abscesses
• Bartonella henselae

Skin/Soft Tissue

• S aureus or Group A Streptococcus
• Pseudomonas
• Fungal soft tissue infection
• Sporotrichosis

Pulmonary

• Tuberculosis
• Fungal infection
• Streptococcus pneumoniae
• Staphylococcus aureus
• Pseudomonas
• Malignancy
• Viral pneumonia
• Autoimmune disease

Prognosis

Pulmonary: Treatment of Mycobacterium avium lung disease is successful in approximately 39% of patients with a 12% 5-year mortality rate. High levels of morbidity and mortality are seen in strains that exhibit macrolide resistance, with a significantly higher 47% mortality rate at 5 years. Pulmonary Mycobacterium abscessus infection outcomes are poor, with only around 41% of patients achieving sputum conversion with surgical and antibiotic intervention. Approximately 34% of patients achieve sputum conversion with antibiotics alone.[11][12]

Lymphadenitis: Children with lymphadenitis caused by Mycobacterium avium are cured in 95% of cases where surgical excision and antibiotic therapy are used.[13]

Skin and Soft Tissue Infection: Resolution of infection is achieved in the vast majority of patients with Mycobacterium marinum, abscessus, ulcerans, fortuitum, and other skin and soft tissue infections when proper antibiotic and surgical treatments are utilized.[1][14][15]

Complications

Mycobacterial lymphadenitis can result in fistula formation and repeated need for surgical intervention. Excision of preauricular nodes risks paralysis of the facial nerve as it courses through the underlying parotid gland. Repeated surgical procedures and scarring from the skin and soft tissue infection can result in cosmetic disfiguration. Since most lymphadenitis cases occur in the neck and facial region lymph nodes in young children, careful consideration of the psychosocial consequences of cosmetic disfiguration from repeated surgical procedures must be weighed against the chances of improved outcomes. The curative rate with antibiotics alone ranges from approximately 66% to 73%, which increases to around 95% with surgical intervention. The ability of patients with advanced age and multiple comorbidities to tolerate the prolonged combination of antibiotic therapy or possible surgical intervention required to treat pulmonary disease necessitates the discussion of chronic suppressive therapy vs. curative therapy. Clarithromycin can cause gastrointestinal upset and may need to be divided into twice-daily dosing. Azithromycin can prolong the QT interval and might have to be avoided due to other medications previously prescribed to patients. Rifabutin can cause leukopenia and uveitis. Ethambutol can cause optic neuritis, and patients should be screened for decreases in visual acuity and color blindness. Severe pulmonary infection resulting in lobectomy can result in chronic respiratory complications even when the intervention is curative.[1][2][16]