Think NTM? Test for NTM

Early diagnosis is critical in the appropriate management of nontuberculous mycobacterial (NTM) lung disease.1-3

Early diagnosis is critical1,9

Despite increasing prevalence, the index of suspicion for NTM lung disease remains low, making early diagnosis an ongoing challenge.4,10-12

NTM lung disease can often be missed due to its nonspecific or overlapping symptomatology in patients with underlying structural lung disease, resulting in NTM being undiagnosed or misdiagnosed.1,3,6,10,11,13

If not diagnosed early enough and left unchecked, NTM lung disease can lead to a decline in lung function, worsening symptoms, and a decrease in overall quality of life for patients.3,8,9,11,14,15

In patients who meet the diagnostic criteria for NTM pulmonary disease, the latest guidelines recommend initiation of treatment rather than watchful waiting, especially in the context of positive AFB sputum smears and/or cavitary lung disease.8

A delay in diagnosis may lead to managing NTM lung disease inappropriately. For instance, many patients may have coexistent NTM and bronchiectasis, and the use of chronic macrolide monotherapy for bronchiectasis may result in macrolide-resistant NTM lung disease.1,3,8,16,17

It takes ~20 months from the first NTM-related symptom or diagnostic procedure to an accurate NTM lung disease diagnosis.5

INSPIRED BY ONE PATIENT’S STORY ISOLATION

Debbie’s undiagnosed NTM symptoms made her feel isolated and alone, driving away her friends and family. Watch “Isolation,” an animation inspired by Debbie’s story.

2020 NTM TREATMENT Guidelines diagnostic criteria

The 2020 NTM Treatment Guidelines require the diagnostic criteria established in the 2007 ATS/IDSA Statement.8

  • Pulmonary or systemic symptoms
  • Exclusion of other diagnoses
  • Nodular or cavitary opacities on chest radiograph, or bronchiectasis with multiple small nodules on chest HRCT scan

NTM lung disease should be considered in the differential diagnosis of patients presenting with7,8:

  • Chronic pulmonary and constitutional symptoms (including chronic cough, sputum production, fatigue, and weight loss)
  • Nodular bronchiectatic and/or fibrocavitary features
Patients who are suspected of having NTM lung disease, but do not meet the diagnostic criteria, should be observed until the diagnosis is firmly established or excluded.8

The 2020 NTM Treatment Guidelines recommend specific management depending on radiographic presentation8

Recognizing susceptible patient types

Examine a nodular bronchiectatic patient

Nodular bronchiectatic patient progression scan
Female Age 70 120 lb
Patient
History
Tests &
Exams
Treatment
Plan

Three years of productive cough, with yellow, brown, and occasionally blood-tinged sputum and chest pain; patient mentioned she was previously diagnosed with bronchiectasis. PCP ordered an AFB smear, which showed a positive result. As symptoms progressed, NTM lung disease was suspected and patient was referred to a pulmonologist.

Physical examination: tall, slender with scoliosis, pectus excavatum; auscultation revealed 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 PCR assay for Mycobacterium tuberculosis

Culture: Mycobacterium avium isolated from 3 sputum samples

Susceptibility testing: susceptible to clarithromycin

Treatment & follow-up: NTM lung disease was treated with a multidrug regimen TIW according to the 2020 NTM Treatment Guidelines

  • Monthly patient visits and sputum cultures
  • Improved clinical symptoms; sputum production became minimal
  • Patient was treated for 6 months and sputum AFB culture was negative previous month

Therapy should continue until patient remains culture negative for 12 months.8

Examine a fibrocavitary patient

Fibrocavitary patient progression scan
Male Age 55 180 lb
Patient
History
Tests &
Exams
Treatment
Plan

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 ID specialist with experience treating NTM.

Physical examination: overweight with wheezing and crackling on auscultation

X-Ray/CT scan:

  • Chest CT scan showed thin-walled cavity in right upper lobe
  • Severe emphysematous changes
  • Stable calcified nodule in right upper lobe and mediastinal lymphadenopathy
  • X-ray and CT scan showed cavitary lesions

AFB smear: positive

Culture: 3 positive samples identified M intracellulare

Susceptibility testing: susceptible to clarithromycin

Treatment & follow-up: NTM lung disease was treated with a multidrug regimen daily according to the 2020 NTM Treatment Guidelines

  • Monthly patient visits and sputum cultures
  • Symptoms improved; sputum production was reduced
  • Sputum continued to be positive for 6 months and adjustments were made to the therapeutic regimen. Four months later, his sputum was still AFB-positive but showed reduced mycobacterial burden
    • This treatment recommendation is consistent with the 2020 Guidelines

Therapy should continue under close monitoring with a goal to achieve sputum conversion to negative.

Examine a recurring lung infection patient

Fibrocavitary patient progression scan
Female Age 70 180 lb
Patient
History
Tests &
Exams
Treatment
Plan

Dry cough for the past 4 years; diagnosed with anemia, asthma, and hyperlipidemia, with family history of TB. Previously treated for pneumonia and TB. Patient was referred to pulmonologist and was diagnosed with NTM lung disease. After treatment initiation, ocular toxicity was detected and treatment was stopped.

Physical examination: overweight with wheezing and crackling on auscultation

X-Ray/CT scan: nodular opacity and bronchiectasis

AFB smear: reported positive in 2 sputum samples

Culture: M avium isolated from 3 sputum samples

Treatment & follow-up: treatment was stopped due to potential side effects. Patient is currently stable with symptoms closely monitored

  • Patient visits every 3 to 6 months
  • Patient did not achieve culture conversion
Patient should be monitored closely for worsening symptoms.

Obtaining a sputum sample

Collecting sputum samples is a key component of the diagnosis and management of NTM lung disease. According to the 2020 NTM Treatment Guidelines, establishing an active monitoring plan that includes regular sputum cultures is recommended whether antibiotic treatment is initiated or delayed (if watchful waiting is the course of action).7,8

While the collection methods can be either invasive or noninvasive, it’s important to tailor the approach depending on the patients and if they are able to readily produce a sample.8

Noninvasive techniques

  • Huff cough
    • The huff cough requires mild to moderate forced exhalation (huff) with open glottis to help expectorate sputum18,19
  • Oscillation
    • PEP devices use collateral ventilation with oscillations to loosen mucus, which can lead to increased sputum clearance18,20
  • Induction
    • Inhalation of isotonic or hypertonic solutions administered by nebulization has been demonstrated to induce a small amount of airway secretion that can be expectorated and analyzed21
      • Pretreatment with a short-acting β2-agonist (dilation aid) is recommended in order to prevent excessive bronchoconstriction
      • The concentration of saline used for sputum induction varies by patient, ranging from 0.9% to 7.0%
      • Cumulative duration of nebulization should be 15 to 20 minutes using an ultrasonic nebulizer for best results
The 2020 NTM Treatment Guidelines recommend collecting ≥3 respiratory samples over at least a week to distinguish NTM lung disease from the occasional presence of NTM in the respiratory tract.8

Invasive technique

  • Bronchoscopy
    • If sputum cannot be obtained through noninvasive methods, a bronchoscopy with or without a lung biopsy may be necessary7,8

Precautions to consider before collecting a sputum sample:

Contamination can occur due to environmental exposure.8

Specimens should be submitted without fixatives.22

Collect samples in sterile, leak-proof, disposable, non-wax containers to avoid contamination, which may produce false positive smear results.22,23

Consider consulting with a respiratory therapist, as needed, for patients who are struggling to produce a viable sputum sample.24

Working with the microbiology lab

Evidence based solely on clinical and radiographic observations is not enough to establish an NTM diagnosis. According to the 2020 NTM Treatment Guidelines, correct identification of NTM is an essential component of the diagnostic process.8

Sputum sample testing procedures for NTM

Test typeDescription
Culture

The 2020 NTM Treatment Guidelines recommend that all cultures for NTM include both solid and broth (liquid) media, the latter allowing higher yield and faster results. Solid media allow observation of colony morphology, growth rates, recognition of >1 mycobacterial species, and quantitation of the infecting organism.7,8,23

Most cultures should be incubated for 2 to 3 weeks, although some may need at least 8 to 12 weeks to determine the type of species and subspecies; however, rapidly growing mycobacteria usually grow within 7 days of subculture.7

AFB smear

The AFB smear test is used in conjunction with the AFB culture test. An AFB smear is a microscopic examination of a specimen that has been stained to detect acid-fast bacteria, such as NTM organisms. This test can provide probable (presumptive) results within 1-2 days.8,25

Sputum cultures should be obtained every 1 to 2 months during the treatment of MAC lung disease to assess response.8

Polymerase chain reaction (PCR)

PCR testing allows rapid detection of drug resistance through the identification of genes associated with resistance and provides preliminary guidance on effective therapy.26,27

This method is used to duplicate copies of a specific DNA sample, allowing scientists to take a very small sample of DNA, which they can then amplify and study in detail.26

REFLEX TESTING MAY BE AVAILABLE

  • Reflex testing refers to additional tests that are automatically performed by a laboratory when initial test results are positive or outside of normal parameters28
    • For example, if an AFB smear and culture are positive, the reflex testing will allow the laboratory to automatically identify the mycobacterial species without having to order species identification separately
  • The laboratory may include all related reflex testing under a single ordering code28
Local and regional laboratories may have their own naming conventions and codes. Contact them to understand how to order these tests.

Requesting speciation and susceptibility panels is important for NTM management decisions

The 2020 NTM Treatment Guidelines recommend identifying NTM isolates down to the species and subspecies level, and not just the group level (eg, Mycobacterium chelonae and M abscessus groups). Correct species- and subspecies-level identification is necessary to accurately assess the clinical significance and severity of isolates. Susceptibility to all relevant drugs should be established for all clinically significant isolates before treatment initiation.8,29

For example, MAC can be classified into distinct species—including M avium and M intracellulare.29-31

The species M abscessus can be further divided into 3 subspecies: M abscessus, M massiliense, and M bolletii, which are increasingly important to identify as each may impact treatment decisions.8

Proper testing procedures continue to evolve to meet the need for more rapid species identification and differentiation. Molecular methods, such as line probe hybridization, polymerase chain reaction-restriction fragment length, polymorphism analysis, and DNA sequencing, have become more popular than traditional biochemical tests or high-performance liquid chromatography.4,8,32

Rapid species and subspecies identification is paramount in order to implement the right treatment regimen.4,8,32

The correlation between in vitro susceptibility testing for MAC and clinical response has only been established for a limited number of antibiotics.8

Steps to consider when collecting sputum:

  1. Collect sputum: Consider the patient’s comfort level and obtain sputum through noninvasive techniques, using invasive only if necessary.8
  2. Work with the microbiology laboratory: Send cultures and request speciation/subspeciation and susceptibility panels at the same time.8
  3. Obtain results from the laboratory: If results cannot be obtained through a commercial laboratory, determine if the collection of additional sputum should be sent to a reference laboratory.7

Reference laboratories with additional technology that aid in NTM specimen analysis may be helpful in certain cases.7

Dr Wendi K Drummond on susceptibility testing

Quality sample criteria

Every laboratory should have specific criteria for accepting and rejecting samples in order to ensure that optimal methods are being followed. It is incumbent on the laboratory to appropriately communicate sample requirements to the physician to ensure the best quality outcome.23

General best practices when submitting to the laboratory:

  • Ensure an adequate amount of specimen is collected by obtaining as much material as possible. An adequate sample of sputum should be thick unlike watery saliva with a volume of 3 mL to 5 mL per sample23
    • A sputum volume of <3 mL or a sample that consists mostly of watery saliva may be rejected

Taking a multidisciplinary approach

NTM lung disease treatment decisions are often difficult, and may require experience managing the disease according to the 2020 NTM Treatment Guidelines. This may mean that a peer consultation or referral to a pulmonologist or ID specialist experienced in the management of NTM lung disease is necessary.4,8,13

To find a specialist with experience managing NTM lung disease, consider the following search tools:

AFB=acid-fast bacilli; ATS=American Thoracic Society; CT=computed tomography; HRCT=high-resolution computed tomography; ID=infectious disease; IDSA=Infectious Diseases Society of America; MAC=Mycobacterium avium complex; NTM=nontuberculous mycobacteria; PCP=primary care physician; PCR=polymerase chain reaction; PEP=positive expiatory pressure; TB=tuberculosis; TIW=three times a week.