Nontuberculous Mycobacterial Lung Disease Challenging to Treat

Living in coastal areas of Florida and California has great appeal for many, with the warm, sunny climate and nearby freshwater and saltwater.

But, unknown to many, those balmy coasts also carry the risk of infection from nontuberculous (atypical) mycobacteria (NTM). Unlike its relative, tuberculosis, NTM is not transmitted from person to person, with one exception: patients with cystic fibrosis.

It is estimated that there were 181,000 people with NTM lung disease in the US in 2015, and according to one study, the incidence is increasing by 8.2% annually among those aged 65 years and older. But NTM doesn’t only affect the elderly; it’s estimated that 31% of all NTM patients are younger than 65 years.

With the warm, moist soil and water, NTM is most commonly found in Florida, California, Hawaii, and the Gulf Coast states. The incidence is somewhat lower in states along the Great Lakes. Other states are not without risk — but NTM is perhaps even more likely to be overlooked in these states by physicians because of a lack of awareness of the disease.



Dr Rebecca Prevots

Rebecca Prevots, PhD, MPH, chief of the epidemiology and population studies unit of the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, told Medscape Medical News, “Why NTM is increasing is one of the most common questions” she gets, followed by whether it is due to climate change. “The short answer is, we don’t know.”

She suggests the increase in diagnoses is due to a combination of increased awareness, host susceptibility, and perhaps environmental changes. One problem is that NTM is not a reportable disease. Also, public health resources have been decimated, both through funding cuts and loss of personnel. Prevots said, “It’s not just NTM surveillance that is important, but you can’t just make a certain condition reportable and expect to have good data without putting resources to it…. Diseases are made reportable at the state level. There’s no mandated reporting up to CDC. So CDC is piloting reporting events through their emerging infectious program.”



Dr Anthony Cannella

Anthony Cannella, MD, assistant professor of infectious diseases at the University of South Florida (USF), is in the midst of NTM. He told Medscape Medical News, “There’s a huge circle with big old dots right over the center of the state.” He is adamant that “a soil-water survey has to occur. We need to know what the devil is happening.”

Florida legislators agreed to allocate $519,000 for NTM testing and surveillance in 2019. But Florida Governor Ron DeSantis vetoed that line item in the budget. WUSF (a National Public Radio affiliate on the USF campus) was unable to get a response to their query about this from the governor’s office.

Who Gets NTM?

Mycobacterium avium complex primarily causes lung disease, which presents as two clinical syndromes.



Dr Kenneth Olivier

“These infections don’t affect everyone,” Kenneth Olivier, MD, MPH, chief, pulmonary clinical medicine, Cardiovascular Pulmonary Branch of the National Heart, Lung, and Blood Institute, told Medscape Medical News. They affect “patients that have underlying genetic conditions that cause abnormalities in the airway clearance mechanisms, particularly cystic fibrosis and primary ciliary dyskinesia, to some extent, patients with COPD.”

The second group is “comprised mainly of postmenopausal women, many of whom have had no predisposing medical problems prior to onset of generally frequent throat clearing or chronic cough, which is what brings them to medical attention.” Olivier added, “Many of these patients have a fairly unique appearance. They tend to have a high prevalence of curvature of the spine, scoliosis, indentation of the chest wall (pectus excavatum), and physical characteristics that overlap heritable connective tissue disorders like Marfan syndrome or Ehlers-Danlos syndrome.”

Olivier pointed out a major problem in NTM diagnosis and treatment: “The guidelines-based approach to chronic cough generally calls for treating postnasal drip, airway reactivity, asthma type symptoms first empirically, before doing different diagnostic studies. That generally causes a delay in obtaining things like CT scan, where you can see the characteristic changes.”

Cannella added, “People are starting to become more aware of it. It’s kind of like pneumocystis back in the 80s…. We’ve had patients who have had long periods of febrile neutropenia, and NTM wasn’t on the radar. Now we’ve picked up at least seven or eight.”

In addition to pulmonary infections, nosocomial outbreaks have occurred, owing to contaminated heater-cooler units, catheter infections, nail salons, or to medical tourism. These more commonly involve rapidly growing species, such as M abscessus, M chelonae, and M fortuitum. Clinicians should also be aware of skin infections from M marinum, which comes from wounds from aquariums, fish, or shellfish. Incubation can occur over months, highlighting the importance of a detailed history and special cultures.

Diagnostics

The diagnosis of NTM is delayed for several reasons. One is the lack of awareness among clinicians about NTM and its risk factors, including hobbies such as gardening or working in places where dirt is aerosolized, such as on road crews, or even from hot tubs. A thorough history is critical.

Another is not recognizing the need for an acid-fast bacilli (AFB) culture, which requires specialized media. Fortunately, NTM can be picked up on fungal cultures, Cannella noted. Clinicians are sometimes discouraged from culturing AFB because doing so may not be cost-effective. And many hospital laboratories are increasingly sending cultures to outside labs, and it can take days — sometimes even more than a week — to receive a report of results.



Dr Charles Daley

Charles Daley, MD, chief of the Division of Mycobacterial and Respiratory Infections at National Jewish Health, expressed his frustration about labs in an interview with Medscape Medical News, saying diagnostics is “an important hole in the US, as our laboratories do not provide clinicians with the results that they need to make good decisions. Most laboratories in the US just don’t speciate the organisms or subspeciate in the setting of abscesses. They don’t tell the clinician enough about the susceptibility, particularly whether there’s inducible resistance. As a clinician, you just don’t have the information to make the right decisions…. We need to improve diagnostics in NTM. Everything is there and available. They just don’t want to do it because it increases the costs.”

Men tend to have fibrocavitary disease, which shows on ordinary chest x-rays, but CT scans are essential for women because women tend to have either nodular disease or bronchiectasis, which does not show on a plain film.

Treatment

A standard treatment for NTM lung disease includes three or four medicationsclarithromycin or azithromycin, rifampin or rifabutin, ethambutol, and streptomycin or amikacin. In vitro resistance is important in predicting the clinical response to a macrolide or amikacin.

For bronchiectatic disease, National Jewish Hospital recommends treatment three times per week rather than daily therapy, as it is better tolerated. Azithromycin is preferred over clarithromycin. Amikacin should be added if there is cavitary or severe disease, and the macrolide is then given daily.

Olivier suggested that physicians stagger the initiation of those drugs to improve the tolerability of the difficult regimen. Generally, treatment is for 18 months — a year after sputum cultures become negative.

If therapy fails — ie, sputum is persistently positive at 6 months — amikacin liposomal inhalation solution (Arikayce) is likely to be added. Patients should be monitored with monthly safety labs, sputum cultures, and an audiogram (if receiving amikacin). Every 3 months, vestibular tests, eye exams, and spirometry should be conducted, and every 6 months, physicians should order a CT, an audiogram, and an electrocardiogram.

Despite completing such a rigorous regimen, about half of patients experience reinfection because of their underlying host susceptibility. Genomic sequencing shows that these are new infections, not relapses, Prevots said. She also noted that gastroesophageal reflux disease is a significant risk factor because of chronic aspiration.

Daley outlined the newer treatments being studied. They include Arikayce, omadocycline, and bedaquiline. He added, “There’s a neutrophil elastase inhibitor trial that’s ongoing, a huge trial. There’s another one looking at basically eosinophilic inflammation.”

Other trials are in the offing, he said, all focusing on the inflammatory response ― a development he described as exciting, because for the longest time, there were few if any NTM trials.

Cannella is also buoyed by the potential synergy of dual beta-lactam therapy with ceftaroline and a carbapenem for M abscessus infections, which are notoriously difficult to treat.

There are unique problems facing drug development for NTM because, for approval, the US Food and Drug Administration (FDA) requires the drug to “improve how a patient feels, functions, or survives.” NTM is associated with low mortality, so that “is off the table,” Daley explained. It’s hard to quantify improvement in function. The top two symptoms to measure are coughing and fatigue, he said. But both are difficult to measure, and some of the medicines worsen cough. Some research groups are now trying to validate patient-reported outcome instruments to satisfy the FDA’s requirements.

Tips for Patients and Physicians

The experts Medscape spoke to had very consistent recommendations for patients.

  • NTM is resistant to chlorine and bromine, so tap water is a major source of infection. Patients should consider increasing the hot water temperature to >130° F and using metal showerheads or bathing rather than showering.

  • Good bathroom ventilation helps.

  • Patients should consider using a water filter that filters entities <5 μ in size — but not carbon filters, which concentrate the organisms.

  • Humidifiers and hot tubs should be avoided.

  • A good face mask, such as an N95, should be worn when gardening or repotting plants.

Olivier stressed that clinicians should familiarize themselves with the guidelines for diagnosing and treating NTM. In particular, clinicians should be aware that using azithromycin for bronchitis might cause resistance in NTM. “Macrolide resistance turns what may be a slowly progressive or bothersome infection into a lethal infection with a 1-year mortality of 35%.”

He concluded, “I would just urge that if the patient’s on their second or third Z-Pak within a year, it’s probably time to look for other causes of what might be happening.”

Cannella, Prevots, and Olivier report no relevant financial relationships. Cannella adds, “My views are not those of my employers, the US Dept of VA or the University of South Florida Morsani College of Medicine.” Daley reports research grants/contracts with AN2, Beyond Air, Bugworks, Insmed, and Paratek and service on advisory boards or as a consultant for AN2, AstraZeneca, Genentech, Insmed, Matinas, Paratek, Pfizer, and Spero.

Judy Stone, MD, is an infectious disease specialist and author of Resilience: One Family’s Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone.

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