ARE NONTUBERCULOUS
MYCOBACTERIA (NTM) OF
CONCERN IN WESTERN PACIFIC
REGION?
WHO TAG Meeting
December 2014 Manila
WWYew
NTM are ubiquitous organisms
present in the environment, notably in
water and soil
In addition, animal
reservoirs are possible
Nontuberculous Mycobacteria (NTM)
• More than 140 species of NTM can cause
infections in human beings and animal, with
20 species representing 95% of all clinical
isolates
• Pulmonary NTM disease is most frequent and
accounts for 65-90% of all clinical NTM
diseases.
Wolinsky E et al
Nontuberculous Mycobacteria and
Associated Diseases
Am Rev Respir Dis (1979)
Colonisation vs Invasion
Yew (2009)
Environmental Exposure to NTM
Contamination
Host local
defence and
systemic
immunity
?
No progression

Transient Colonisation
Pathogen virulence ?
Host local defence
impairment∆ ?
Active Colonisation
Mycobacterial
load ?
Other host
cofactors* ?
Indolent Infection
Host
susceptibility,
local / systemic
impairment of
immunity
?
∆ e.g. COPD, Pneumoconiosis, Cystic Fibrosis
* Bacterial infection, TB, Lung cancer, Tobacco
Smoke, Alcohol etc
? Bronchiectasis
Overt Disease
(PULMONARY)
Risk Factors for Pulmonary NTM Disease
• Pneumoconiosis
• COPD
• Cystic fibrosis
• BRONCHIECTASIS
• HIV
• Systemic immunocompromisation
• Achalasia and other oesophageal dysmotility
• Pulmonary alveolar proteinosis
• Alpha-1-antitrypsin deficiency
• Body habitus characteristics
• Gastroesophageal reflux
• Familial
• Idiopathic
Pathogenicity/ Virulence
M. kansasii Lung Disease
M. szulgai Lung
Disease
M abscessus
Lung Disease
In a Patient with
Lung Transplant
M abscessus Lung Disease in an Old Patient after His Lately Visit to Hot Spring !!
ATS / IDSA Statement:
Diagnosis,
Treatment and Prevention of NTM Diseases
Am J Respir Crit Care Med (2007)
Clinical and Microbiologic Criteria for Diagnosing NTM
Lung Disease (Adapted) [1]
Clinical and Radiographic (both required)
1. Pulmonary symptoms, nodular or cavitary
opacities on CXR, or a HRCT scan that shows
multifocal bronchiectasis with multiple small
nodules
AND
2. Appropriate
exclusion
of
other
diagnoses
especially TB and mycosis
ATS / IDSA Statement:
Diagnosis,
Treatment and Prevention of NTM Diseases
Am J Respir Crit Care Med (2007)
Clinical and Microbiologic Criteria for Diagnosing NTM
Lung Disease (Adapted) [2]
Microbiologic
1. Positive culture results from at least two separate expectorated sputum
samples. If the results from (1) are nondiagnostic, consider repeat
sputum AFB smears and cultures
OR
2. Positive culture result from at least one bronchial wash or lavage
OR
3. Transbronchial or other lung biopsy with mycobacterial histopathologic
features (granulomatous inflammation or AFB) and positive culture for
NTM, or biopsy showing mycobacterial histopathologic features
(granulomatous inflammation or AFB) and one or more sputum or
bronchial washings that are culture positive for NTM
FIBROCAVITARY
MAC Lung Disease
In a Middle-Age
Male Smoker
NODULAR BRONCHIECTASIS due to MAC in an Elderly Woman
Koh WJ Clinical Significance of a Single Isolation of
Pathogenic NTM from Sputum Specimens
Diagn Microbiol Infect Dis (2013)
• 120 patients with MAC, 62 patients with M
abscessus and 8 patients with M kansassii as a
single positive sputum culture were followed
up.
Bronchiectasis
• 26 patients: 16 MAC and 10 M abscessus
(14%) had an additional positive culture of the
same NTM species and met the ATS diagnostic
criteria for NTM lung disease
Possible Causes of Rise in Prevalence of
NTM Infection / Disease Worldwide
 Increase in prevalence of HIV infection and other
acquired immunocompromised states
 Increased understanding and
organisms as potential pathogens
awareness
of
 Increased recognition of association of these
mycobacteria with a number of pulmonary and
extrapulmonary
conditions,
as
well
as
pathophysiology of ageing
 Improvement in methods of detection and recovery
 Increasing contact of humans with these organisms
worldwide
Another possible association of
increase in prevalence of
Pulmonary NTM
Infection/Disease?
• Decrease of prevalence of TB and/or
• Decrease of BCG vaccination
Hoefsloot W, van Ingen J, Andrejak C et al
The Geographic Diversity of NTM isolated from Pulmonary Samples : A
NTM-NET Collaborative Study Eur Respir J (2013)
• Worldwide Study in 2008………. Data from
20182 patients (91 NTM species) from 62
laboratories in 30 countries
• MAC predominated in most countries,
followed by M gordonae and M xenopi
• Important differences in geographical
distribution of MAC species as well as M
xenopi, M kansasii, and Rapidly Growing
Mycobacteria
Hoefsloot W et al ERJ 2013
• Worldwide, RGM account for 10-20% of all
NTM isolates . In USA, M abscessus complex
ranks as the second most common cause of
NTM lung disease, but its prevalence is even
higher in East Asian countries such as Korea
and Japan.
Proportions of M abscessus, M massiliense and M bolletii
in M abscessus complex
Koh, Stout, Yew IJTLD (2014) Adapted
Author year
Country
M abscessus
M massiliense M bolletii
Van Ingen
2009
Netherlands
64%
21%
15%
Yoshida 2013
Japan
63%
35%
2%
Nakanaga
2014
Japan
60%
37%
3%
Koh 2011
Korea
44%
55%
1%
Lee 2014
Korea
50%
49%
1%
ASIA
39%
ASIA
3%
6%
ASIA
Thomson RM et al Changing Epidemiology of
Pulmonary Nontuberculous Mycobacteria
Infections Emerg Infect Dis (2010)
• The incidence of notified cases of clinically
significant pulmonary disease rose from 2.2 per
100,000 in 1999 to 3.2 per 100,000 in 2005 in
Queensland
• The pattern of disease has changed from
predominantly cavitary disease in middle-aged
men who smoke to fibronodular disease in
elderly women.
• Mycobacterium intracellulare is the main
pathogen associated with the increase
USA
Thomson R et al Isolation of NTM from Houshold
Water and Shower Aerosols in Patients with
Pulmonary Disease Caused by NTM
J Clin Microbiol (2013)
• The mycobacteria isolated from 20 patients included M
avium (5), M intracellulare (12), M abscessus (7), M
gordonae (1), M lentiflavum (1), M fortuitum (1), M
peregrinum (1), M chelonae (1), M triplex (1) and M
kansasii (1)
• Pathogenic mycobacteria were isolated from 19 homes.
Species identified in the home matched that found in the
patient in 7 (35%) cases. M abscessus (3), M avium (1), M
gordonae (1), M lentiflavum (1) and M kansasii (1)
• NTM from the aerosols included M abscessus (3 homes),
M gordonae (2 homes), M kansasii (1 home), M fortuitum
complex (4 homes), M mucogenicum (1 home), M
wolinsky (1 home).
Thomson RM et al Factors Associated with the
Isolation of NTM from a Large Municipal Water
System in BRISBANE Australia BMC Microbiol (2013)
• Species that have been documented to cause disease in
humans residing in Brisbane that were also found in water
include M gordonae, M kansasii, M abscessus, M chelonae,
M fortuitum complex, M intracellulare, M avium, M
flavescens, M interjectum, M lentiflavum, M
mucogenicum, M simiae, M szulgai, M terrae, with M
kansasii frequently isolated . M avium and M
intracellulare were only infrequently isolated.
• Distance of sampling site from water treatment plant in
summer was associated with isolation of NTM. Pathogenic
NTM were more likely identified from sites with narrower
pipes, predominantly distribution sample points and from
sites with asbestos cement or modified PVC pipes.
Simons S et al Nontuberculous Mycobacteria in Respiratory
Tract Infections, EASTERN ASIA.
Emerg Infect Dis (2011)
• MAC was most frequently isolated (13%-81%)
and was the commonest cause of pulmonary
NTM disease (43%-81%). Also pathogenic
were the rapidly growing mycobacteria.
Among all NTM isolated from pulmonary
samples, 31% were considered clinically
relevant……most patients were male (79%)
and had history of TB (37%)………
Jing H et al Prevalence of Nontuberculous
Mycobacteria Infection, China, 2004-2009 (1)
Emerg Infect Dis (2012)
• In Shanghai, the prevalence of NTM (by
isolation among all mycobacteria) increased
from 4.26% in 2005 to 6.38% in 2008.
• To investigate the NTM prevalence in rural
China, the NTM isolation rates, species
distribution and drug resistance profiles
through a population-based TB sentinel
surveillance study in Shandong, the second
largest province in China was undertaken.
Jing H et al Prevalence of Nontuberculous
Mycobacteria Infection, China, 2004-2009 (2)
Emerg Infect Dis (2012)
• From 2004 through 2009, mycobacteria species
were isolated from sputum specimens of 3949
patients with suspected pulmonary TB
• The conventional biochemical testing of these
specimens identified 68 NTM isolates, of which
64 were confirmed by 16S rRNA gene
sequencing : 52 (81.2%) were M intracellulare, 5
(7.8%) were M kansasii, 3 (4.7%) were M
fortuitum, 2 (3.1%) were M chelonae and 1
(1.6%) was M gordonae and M scrofulaceum,
respectively.
Jing H et al Prevalence of Nontuberculous
Mycobacteria Infection, China, 2004-2009 (3)
Emerg Infect Dis (2012)
• NTM isolation rate was lower in the rural area:
1.6% only, and was more stable than that for
urban area (e.g. 5.09% in Shanghai)
• The NTM strains were found in 30.7% of
suspected MDR-TB cases, and 4.0% of
retreatment cases were clinically significant
NTM infections
• Thus the findings suggest that pulmonary NTM
colonization/infection pose substantial
difficulties in the clinical management of NTM
infections and MDR-TB.
Lai CC et al Nontuberculous Mycobacteria Infections in
Cancer Patients in a Medical Center in Taiwan, 2005-2008 (1)
Diagn Microbiol Infect Dis (2012)
• A total of 219 cancer patients with NTM
infections : 60.7% > 65 years, mostly male
• Lung cancer, followed by haematological
malignancy and gastrointestinal cancer
• Pulmonary NTM infection accounted for
93.6%, followed by skin and soft tissue
infections (3.2%), disseminated infections
(1.8%) and genitourinary tract infection (1.4%)
Lai CC et al Nontuberculous Mycobacteria Infections in
Cancer Patients in a Medical Center in Taiwan, 2005-2008 (2)
Diagn Microbiol Infect Dis 2012
• Disseminated infections occurred exclusively
in patients with haematological malignancy
• MAC caused most lung diseases and M
abscessus was the most common pathogen
for extrapulmonary disease
Lai CC et al Clinical Significance of Nontuberculous Mycobacteria
Isolates in ELDERLY Taiwanese Patients Eur J Clin Microbiol 2011
• NTM colonization was found in 80.4% (1339
subjects) and only 19.4% had NTM diseases.
• The annual incidence rates (per 100,000 inpatients
and outpatients) of NTM colonization and disease
both increased significantly (P<0.0001) from 10.5 to
15.8 and from 2.1 to 4.3, respectively.
• Isolated pulmonary NTM diseases accounted for 90.2
% of NTM cases, with MAC being the most prevalent
organisms, followed by M abscessus
Khann S et al Linkage of Presumptive MDR-TB Patients
to Diagnostic and Treatment Services in Cambodia
PLoS One 2013
• Of 19236 patients registered, 2% fufilled the criteria
of presumptive MDR-TB , 187 (48%) were examined
for culture. This proportion was higher among relapse,
failure, return after default and nonconverters at 3
mo of new smear-positive TB patients (>60%) as
compared to nonconverters at 2 months of new TB
cases (<20%)
• Nearly 2/3 (113) of the samples were culture positive;
of these, ¾ (85) grew MTB complex and
(28) grew
NTM.
• 21 cases were diagnosed as MDR-TB (all among
retreatment TB cases and none from nonconverters)
¼
NTM Research Project in Kampong Cham
Preliminary Results
MSF* with collaborating
organizations
• Apparent increase in NTM recovery since
introduction of liquid media in laboratories in
Cambodia (2009)
• Survey of prevalence of NTM appears warranted
• Study and treatment of pulmonary NTM diseases
would be beneficial to patients and the medical
community
*Maryline Bonnet
Maryline.BONNET@epicentre.msf.org
NTM Research in Kampong Cham (1)
• To delineate pulmonary NTM colonization
versus disease in PULMONARY TB SUSPECTS
•
•
•
•
•
Assessment of subject comprises
Questionnaire on epidemiology and clinical history
Physical examination
CXR
3 sputum specimens over 2 consecutive days for smear, culture on
LJ and MGIT, and back-up storage (for culture)
• Speciation of mycobacteria isolated by GenoType Mycobacteium
CM/AS
• Further speciation and drug susceptibility testing at central
reference laboratory
NTM Research in Kampong Cham (2)
• NTM disease diagnosed by
• ATS 2007 Guidelines (clinical, radiological and
microbiological criteria) : investigations
limited to sputum specimens and also CXR
• Consensus of participating experts
• NTM colonization, otherwise
NTM Research in Kampong Cham (3)
•
•
•
•
•
•
•
1186 subjects
Mean age 54 yrs
Female 51.6%
Farmers 43.0%
HIV positive 2.3%
Current smoker or ex-smoker 37.1%
Past TB history 26.0%
NTM Research in Kampong Cham (4)
• 126 out of 1186 patients (10.6%) had at least one
positive culture isolate of NTM
• 120/126 NTM isolates were speciated using the
alluded molecular technique
• 21.7% M fortuitum
• 15.8% M intracellulare
• 12.5% M abscessus
• 10.8% M gordonae
• 10.8% M scrofulaceum
• 8.3% M simiae
• 1.7% M avium
NTM Research in Kampong Cham (5)
• 11 out of 126 patients (9.0%) were diagnosed
to have NTM lung disease
• 7 patients had previous TB with severely
destroyed lungs
• 4 patients had HIV infection (with MAC)
Maiga M et al Failure to Recognize Nontuberculous
Mycobacteria Leads to Misdiagnosis of Chronic
Pulmonary TB
PLoS One (2012)
• Of 142 TB patients enrolled, 43% were clinically
classified as retreatment cases, and 12% of
cultured isolates were NTM (8% with NTM
disease: 8 MAC, 2 M simiae, and 1 M palustre,
with all categorised as retreatment cases); the
remaining 4% NTM isolates were in patients
who also had TB. These were all new cases.
• Among the cases with MAC isolated, only 3 had
HIV positivity.
Aliyu G et al Prevalence of Nontuberculous
Mycobacterial Infections among TB Suspects in
Nigeria
PLoS One (2013)_
• Of 1603 patients screened, 444 (28%) culture-positive
cases of PTB were identified. Of these, 375 (85%)
were due to strains of MTB complex and 68 (15%)
were due to NTM.
• In contrast to TB, NTM cases were more likely to be
diagnosed during the calendar months of the
Harmattan dust season (OR 2.34, P=0.01) and aged
older than 35 years (OR 2.77, P=0.0007) but less likely
to have AFB identified on smear (OR 0.06, P<0.0001).
Among those with NTM infections, cases 35 years or
younger were more likely to have co-infection with
HIV (OR 3.76, P=0.0009)
McCarthy KD et al Nontuberculous Mycobacterial
Disease in Patients with HIV in Southeast Asia.
Am J Respir Crit Care Med (2012)
• Of 1060 patients enrolled in Thailand and Vietnam,
where liquid culture was performed, 124 (12%) had
TB and 218 (21%) had NTM. Of 218 subjects with
NTM, 66 (30%) were classified as NTM pulmonary
disease suspects, 9 (4%) with NTM pulmonary
disease, and 10 (5%) with NTM disseminated disease.
The prevalence of NTM pulmonary disease was 2%
(19/ 1060).
• Of 51 patients receiving antiretroviral therapy, none
had NTM disease, compared with 19 (2%) of 1009 not
receiving ART.