September/October 2018

When It's More Than Just a Cough
By Paul Streck, MD
Today's Geriatric Medicine
Vol. 11 No. 5 P. 12

NTM lung disease, a progressive and debilitating condition that predominantly affects older adults, is growing in prevalence.

Have you heard your patients with persistent coughing, fatigue, and shortness of breath say things such as the following?:

• "I would cough in public and all eyes were on me."

• "Every cough felt like it was going to break me."

• "When breathing is out of your control, it's all you can think about."

• "It felt like my cough was holding me prisoner."

• "The exhaustion—it was in control, making decisions for me."

If the answer is yes, they may be suffering from a progressive and debilitating lung disease that's on the rise—increasing by 8% each year—and disproportionately affecting older adults.1 Nontuberculous mycobacterial (NTM) lung disease is caused by inhaling contaminated aerosols from the environment. The condition can often be misdiagnosed—or sometimes undiagnosed completely—due to its nonspecific or overlapping symptomatology with other lung conditions.

In 2018, an estimated 75,000 to 105,000 patients will be diagnosed with NTM lung disease in the United States, making the disease more widespread than tuberculosis (TB).2,3 Those most vulnerable to contracting the disease are people aged 65 and older—a population that's expected to nearly double by 2030—and patients with underlying lung conditions.4

What Are Nontuberculous Mycobacteria?
Found in the water and soil, mycobacteria are common throughout the environment, though they do not usually cause illness. NTM bacteria can be found in tap water, showerheads, steam from hot tubs, and soil from parks and gardens.

Everyone comes into contact with NTM bacteria during their daily lives by breathing it in through their noses and mouths. One US study across 25 states showed that NTM bacteria were found in nearly eight of 10 water samples.5 Most people are not infected, however, because their lungs are healthy enough to clear the bacteria.

There are many different species of NTM that can cause an infection. Among the almost 200 different species of NTM identified, the most common pathogens for lung disease in the United States are Mycobacterium avium complex (MAC), M kansasii, and M abscessus. NTM bacteria are most commonly classified by growth rate—either slowly growing (eg, MAC, M kansasii, M xenopi) or rapidly growing (eg, M abscessus, M fortuitum, M chelonae). In the United States, MAC accounts for more than 80% of all NTM lung disease cases.6

When NTM Becomes Harmful
When inhaled, NTM can invade lung tissue and intracellular pulmonary compartments—specifically, macrophages—where they disrupt normal cellular defense mechanisms by inhibiting the formation of phagolysosomes, which play a role in NTM destruction. This allows the bacteria to create a reservoir in the lungs. NTM can also live extracellularly where free-floating bacteria form biofilm colonies in the lungs. Collectively, these mechanisms allow NTM to be resilient in the body.

NTM will persist within lung tissue and macrophages, causing chronic, indolent infection and progressive lung destruction. In some cases, it can cause severe or even permanent damage to the lungs. In a long-term observational study of 40 patients with untreated nodular bronchiectatic MAC lung disease, serial CT scans demonstrated significant radiologic deterioration in 39 patients (97.5%) over a mean follow-up of approximately six years.7

NTM lung disease has been associated with a 4.3-fold higher incidence of respiratory failure and an increase in mortality rates when compared with the general population.8,9 According to one study evaluating more than 1,000 patients, the overall three-year cumulative death rate of NTM was 34%.10,11

Other studies evaluating NTM lung disease found the following:
• The five-year mortality rate was 35%, according to a study of 316 patients with NTM respiratory isolates.9

• A study using a data set of 2.3 million Medicare beneficiaries found that patients with NTM were 40% more likely to die over the 10-year study period than were patients without NTM.4

In addition to the risk of mortality associated with NTM lung disease, the financial cost of NTM lung disease is another harmful factor for patients and the health care system. According to a study using Medicare beneficiary data and US Census Bureau data, the associated cost of NTM lung disease was $1.7 billion for more than 181,000 cases of NTM lung disease in the United States in 2014.1 The majority of the costs for treating NTM lung disease are due to antibiotic prescription costs. In a study using Medicare beneficiary data, prescription medications accounted for 76% of the estimated $815 million costs associated with NTM lung disease in 2010.1

Know Who Is at Risk
People who are at greater risk of contracting NTM lung disease include the following:

• patients with bronchiectasis, COPD, or asthma;

• slender, elderly women with Marfanoid body habitus (eg, Lady Windermere syndrome); and

• patients who may be immunocompromised or have specific genetic disorders that cause structural lung damage that can impair airway and mucus clearance.

These susceptible individuals may have impaired airway or mucus clearance that aids the growth and survival of NTM.

NTM lung disease is more common in women, and those living in certain geographic regions may also be more susceptible. Seven of 10 NTM infections in the United States occur along a coastal area, and one-half of diagnosed NTM lung disease patients reside within one of only seven states: Florida, New York, Texas, California, Pennsylvania, New Jersey, and Ohio.

How to Recognize Susceptible Patients
Symptoms of NTM lung disease vary but can include chronic coughing, fatigue, dyspnea, weight loss, fever, and chest pain. Patients may have difficulty breathing and sleeping, feel weak, and struggle with physical activity. These symptoms will worsen over time despite medical interventions.

Because the signs and symptoms of NTM lung disease often overlap with underlying lung conditions that increase risk for NTM, the disease is sometimes misdiagnosed or not diagnosed at all.

When examining patients who may be showing the signs and symptoms, be mindful of these common comorbidities.

1. Bronchiectasis and NTM
Up to one-half of patients with bronchiectasis also have an NTM infection.12,13 Bronchiectasis increases susceptibility for NTM, and NTM infections are likely to exacerbate the underlying bronchiectasis, making both conditions more difficult to treat. Research shows that NTM is more common in patients with noncystic fibrosis bronchiectasis.12 Regular screening for NTM in this population is recommended.

Case Study: Nodular Bronchiectatic Patient14
Gender: Female
Age: 70
Weight: 120 lbs
Patient History: Patient with three years of productive cough, with yellow, brown, and occasionally blood-tinged sputum and chest pain; previously diagnosed with bronchiectasis. Primary care physician ordered an acid-fast bacilli (AFB) smear, which showed a positive result. As symptoms progressed, NTM was suspected and patient was referred to a pulmonologist.
Physical Examination: Tall, slender, scoliosis, pectus excavatum; auscultation: mitral valve prolapse, wheezing, and crackles.
X-ray/CT Scan: Showed nodular opacities with local bronchiectasis and local cystic bronchiectasis.
AFB Smear: Positive, but negative polymerase chain reaction assay for Mycobacterium tuberculosis.
Culture: M avium isolated from three sputum samples.

2. COPD and NTM
People with COPD are particularly susceptible to NTM lung disease. Results of a population-based, case-controlled study show that COPD may increase the risk of an NTM lung infection by 15.7-fold. More than one-half of COPD patients in the study were hospitalized for exacerbations within the previous year.11

Case Study: Fibrocavitary Patient14
Gender: Male
Age: 55
Weight: 180 lbs
Patient History: Patient with one year of progressive cough with greenish sputum; treated for pneumonia with multiple antibiotics without symptomatic improvement. Patient is currently a smoker and has severe COPD. Positive sputum culture showed AFB and confirmed infection with Mycobacterium intracellulare. Patient was referred to an infectious disease specialist with experience treating NTM.
Physical Examination: Overweight, wheezing, and cracklings on auscultation.
X-ray/CT Scan: Chest CT scan showed thin-walled cavity in right upper lobe; severe emphysematous changes; and stable calcified nodule in right upper lobe and mediastinal lymphadenopathy. X-ray and CT scan showed cavitary lesions.
AFB Smear: Positive
Culture: Three positive samples identified M intracellulare.

3. Asthma and NTM
Asthma patients are nearly eight times more likely to contract an NTM infection.11 Particularly, studies demonstrate an increased risk in patients whose asthma is hard to control and in those who are older, have more severe airflow limitations, and are treated with higher doses of inhaled corticosteroids for longer periods. NTM infections associated with asthma may be underrecognized and should be part of the differential diagnosis in difficult-to-treat patients.

Case Study: Patient With Recurring Infections14
Gender: Female
Age: 70
Weight: 180 lbs
Patient History: Patient with dry cough for the past four years; diagnosed with anemia, asthma, hyperlipidemia, with family history of TB. Treated previously for pneumonia and TB. The patient was referred to a pulmonologist and was diagnosed with NTM. After treatment initiation, ocular toxicity was detected and treatment was stopped.
Physical Examination: Overweight, wheezing, and cracklings on auscultation.
X-ray/CT Scan: Nodular opacity and bronchiectasis.
AFB Smear: Reported positive in two sputum samples.
Culture: M avium isolated from three sputum samples.

Early Diagnosis Is Key
Despite increasing prevalence, the index of suspicion for NTM lung disease remains low, making early diagnosis an ongoing challenge.

On average, it can take nearly two years (20 months) from the first related symptom or diagnostic procedure for a health care professional to accurately diagnose NTM lung disease. And by the time they are diagnosed, two out of three patients have developed moderate-to-severe NTM. A delayed diagnosis can lead to antibiotic resistance from inappropriate treatment.

It's necessary to identify the NTM species and subspecies to accurately assess the clinical significance and severity of isolates. For example, MAC can be classified into distinct species, including M avium and M intracellulare.

The American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) have issued diagnostic recommendations that state if a patient presents with the following clinical, radiographic, and microbiologic criteria, it's likely the person has NTM lung disease:

Clinical and Radiographic Criteria:
• bronchopulmonary symptoms, nodular or cavitary opacities on chest radiograph, or multifocal bronchiectasis with multiple small nodules on chest high-resolution computed tomography scan; and

• exclusion of other diagnoses.

Microbiologic Criteria:
• positive culture results from at least two separate expectorated sputum samples;

• positive culture result from at least one bronchial wash or lavage; or

• transbronchial or other lung biopsy with mycobacterial histopathologic features and positive culture for NTM or biopsy showing mycobacterial histopathologic features and one or more sputum or bronchial washings that are culture-positive for NTM.

NTM treatment decisions can be complex and influenced by a provider's experience with the disease; therefore, a peer consultation or referral to a pulmonologist or infectious disease specialist may be the best course of action.

Once a patient and provider have agreed on the appropriate treatment course, therapy goals will vary depending on the clinical presentation and patient needs. For some, both microbiologic and clinical improvement are possible; for others, suppressive treatment strategies may be more appropriate. The ATS/IDSA statement defines treatment success as sustained culture conversion, improved symptoms, and achieved radiologic improvement.

Conclusion
NTM lung disease is a rare and serious disorder associated with increased rates of morbidity and mortality. While most people do not become infected with NTM, keep the condition top of mind as you encounter patients in your clinical practice who show the signs and symptoms, especially elderly patients who reside in coastal regions and those with underlying lung conditions. Left untreated, NTM lung disease can lead to a serious decline in lung function, worsening symptoms, and decreased quality of life.

Visit NTMfacts.com for more information on NTM lung disease and additional resources.

— Paul Streck, MD, is the chief medical officer of Insmed Incorporated, a global biopharmaceutical company focused on the unmet needs of patients with rare diseases. He brings more than 25 years of clinical development, management, and leadership expertise.

NTM LUNG DISEASE SYMPTOMS
• Chronic coughing
• Fatigue
• Dyspnea
• Weight loss
• Fever
• Chest pain

NTM LUNG DISEASE RISK FACTORS
Patients with one of the following preexisting chronic respiratory problem and susceptibility factors are at a higher risk for getting NTM:
• Bronchiectasis, COPD, or asthma
• Slender, elderly women with Marfanoid body habitus (eg, Lady Windermere syndrome)
• Compromised immune system

EFFECTS OF NTM LUNG DISEASE
• Reduces patients' quality of life
• Exacerbates the deterioration of lung function, compounding existing lung conditions
• Contributes to progressive, irreversible lung destruction

— SOURCE: NTMFACTS.COM

References
1. Strollo SE, Adjemian J, Adjemian MK, Prevots DR. The burden of pulmonary nontuberculous mycobacterial disease in the United States. Ann Am Thorac Soc. 2015;12(10):1458-1464.

2. Mirsaeldi M, Sadikot RT. Gender susceptibility to mycobacterial infections in patients with non-CF bronchiectasis. Int J Mycobacteriol. 2015;4(2):92-96.

3. Insmed Incorporated. NTM and where you live. https://www.aboutntm.com/who-is-at-risk/

4. Adjemian J, Olivier KN, Seitz AE, Holland SM, Prevots DR. Prevalence of nontuberculous mycobacterial lung disease in U.S. Medicare beneficiaries. Am J Respir Crit Care Med. 2012;185(8):881-886.

5. Donohue MJ, Mistry JH, Donohue JM, et al. Increased frequency of nontuberculous mycobacteria detection at potable water taps within the United States. Environ Sci Technol. 2015;49(10):6127-6133.

6. Adjemian J, Prevots DR, Gallagher J, Heap K, Gupta R, Griffith D. Lack of adherence to evidence-based treatment guidelines for nontuberculous mycobacterial lung disease. Ann Am Thorac Soc. 2014;11(1):9-16.

7. Park TY, Chong S, Jung JW, et al. Natural course of the nodular bronchiectatic form of Mycobacterium Avium complex lung disease: long-term radiologic change without treatment. PLoS One. 2017;12(10):e0185774.

8. Yeh JJ, Wang YC, Lin CL, et al. Nontuberculous mycobacterial infection is associated with increased respiratory failure: a nationwide cohort study. PLoS One. 2014;9(6):e99260.

9. Novosad SA, Henkle E, Schafer S, et al. Mortality after respiratory isolation of nontuberculous mycobacteria. A comparison of patients who did and did not meet disease criteria. Ann Am Thorac Soc. 2017;14(7):1112-1119.

10. Andréjak C, Thomsen VØ, Johansen IS, et al. Nontuberculous pulmonary mycobacteriosis in Denmark: incidence and prognostic factors. Am J Respir Crit Care Med. 2010;181(5):514-521.

11. Andréjak C, Nielsen R, Thomsen VØ, Duhaut P, Sørensen HT, Thomsen RW. Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis. Thorax. 2013;68(3):256-262.

12. Mirsaeidi M, Hadid W, Ericsoussi B, Rodgers D, Sadikot RT. Non-tuberculous mycobacterial disease is common in patients with non-cystic fibrosis bronchiectasis. Int J Infect Dis. 2013;17(11):e1000-e1004.

13. Tanaka E, Amitani R, Niimi A, Suzuki K, Murayama T, Kuze F. Yield of computed tomography and bronchoscopy for the diagnosis of Mycobacterium avium complex pulmonary disease. Am J Respir Crit Care Med. 1997;155(6):2041-2046.

14. Insmed Incorporated. Recognizing susceptible patient types. NTM facts website. https://www.ntmfacts.com/think/#profiles