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REVIEW
Varying clinical presentations of nontuberculous mycobacterial
disease : Similar to but different from tuberculosis
Tsutomu Shinohara1, 2, 3, Shun Morizumi1, 2, and Kenya Sumitomo2
Department of Community Medicine for Respirology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan,
Division of Internal Medicine, Japan Agricultural Cooperatives Kochi Hospital, Kochi, Japan, 3Department of Clinical Investigation, National Hospital Organization Kochi Hospital, Kochi, Japan
1

2

Abstract : The incidence rate of pulmonary nontuberculous mycobacterial disease (PNTMD) in Japan is the highest among major industrialized nations. Although the typical clinical course and radiological manifestations of
PNTMD are different from those of pulmonary tuberculosis (TB), confusion about these mycobacterial diseases
leads to a diagnostic pitfall. Diagnostic challenges include the coexistence of Mycobacterium tuberculosis (MTB)
and nontuberculous mycobacteria (NTM), false positives for NTM in MTB nucleic acid amplification tests, microbial substitution, and abnormal radiological manifestations caused by NTM. Features of extrapulmonary NTM
diseases, such as pleurisy, vertebral osteomyelitis, and disseminated disease, are different from the corresponding tuberculous diseases. Moreover, the immunological background of the patient (status of human immunodeficiency virus infection with or without antiviral therapy, continuation or discontinuation of immunosuppressive
therapy, use of immune checkpoint inhibitor, pregnancy and delivery, etc.) influences the pathophysiology ofmycobacterial diseases. This review describes the varying clinical presentations of NTM disease with emphasison the differences from TB. J. Med. Invest. 68 : 220-227, August, 2021
Keywords : nontuberculous mycobacteria, tuberculosis, acid-fast bacteria tests, extrapulmonary diseases, immune reconstitution inflammatory syndrome

INTRODUCTION
The incidence rate of pulmonary nontuberculous mycobacterial disease (PNTMD) in Japan during 2014 was estimated to
be 14.7 cases per 100,000 person-years, exceeding that of culture-positive pulmonary tuberculosis (PTB) for the first time (1).
This rate was the highest among major industrialized nations(2). Patients with PNTMD generally have a long disease course
and the estimated PNTMD prevalence in Japan is greater than
110 cases per 100,000 persons, suggesting the increasing importance of cooperation between respiratory specialists and general
physicians.
On the other hand, many physicians in Japan may lack knowledge about acid-fast bacteria (AFB) tests due to the decreasing
number of tuberculosis (TB) patients. Furthermore, when physicians with little experience in treating TB patients provide
medical care to patients with nontuberculous mycobacteria(NTM), they may confuse these mycobacterial diseases, leading
to a diagnostic pitfall.
In addition, the general use of biological products for autoimmune and malignant diseases has led to an increase of mycobacterial diseases in patients whose immune response was alteredby therapeutic agents. Therefore, physicians need to be remindedthat they may encounter mycobacterial disease regardless of
their specialty. This review describes the varying clinical presentations of NTM disease, and discusses the challenges of AFB
tests and points to keep in mind when providing medical care topatients with NTM.

Received for publication December 8, 2020 ; accepted March 22, 2021.
Address correspondence and reprint requests to Tsutomu Shinohara,
MD, PhD., Department of Community Medicine for Respirology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan andFax : +81-88-863-2186.

DIAGNOSTIC CHALLENGES IN PULMONARY MYCOBACTERIAL DISEASESThe typical clinical course and radiological manifestations of
PNTMD are different from those of PTB, and the differential
diagnosis between these infections can be simplified by identifying the mycobacterial species detected from the patient anduse of supplementary methods such as Mycobacterium tuberculosis(MTB) antigen specific interferon-γ release assay (IGRA) andmeasurement of antibodies to the glycopeptidolipid (GPL) core
antigen specific to Mycobacterium avium complex (MAC) (3-5).
However, diagnostic pitfalls may cause physicians to make anincorrect initial diagnosis. Some of the diagnostic challenges of
pulmonary mycobacterial diseases are as follows :Erroneous diagnosis of multidrug-resistant tuberculosis (MDR-TB)
caused by the presence of NTM
In Japan, MDR-TB, defined as the disease caused by MTB
resistant to isoniazid and rifampicin, accounts for less than 1%of new TB cases (6, 7). As patients with MDR-TB are refractory
to treatment, information about drug-susceptibility tests (DST)
is important in clinical practice (6). However, the results of DST
may not always reflect the subsequent clinical course. The diagnosis of MDR-TB was reported to be incorrect in 9 (13%) of 70
patients possibly due to laboratory-related errors (8). Situations
that are considered to be laboratory-related errors include a goodtreatment course with standard regimens, disagreement with
the DST results on resubmitted specimens, detection of MDRTB from untreated inactive lesions, and a lack of tuberculous
lesions. Coexistence of NTM with MTB in sputum, cross-contamination, and specimen mislabeling could be the cause (8, 9).
Misdiagnosis of MDR-TB may cause serious harm to the patient
because it will result in the unnecessary abandonment of aneffective treatment. It is thus important to carefully observe thesolid media to distinguish between colonies of NTM (smoothtype) and MTB (rough type), and share information about the

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The Journal of Medical Investigation Vol. 68 August 2021
patient’s background and clinical course between laboratory
staff and the physicians to avoid misdiagnosis.

False positives for NTM in MTB nucleic acid amplification tests(NAATs)An important part of the initial assessment of suspected pulmonary mycobacterial disease is the determination of whether
it is PTB exhibiting human-to-human transmission. Currently,
MTB NAATs are mainly used for rapid diagnosis (7 kits are
currently available in Japan), and their sensitivities in patientswith sputum smear-positive or negative PTB are 94-100% and62-80%, respectively (10, 11). They also have excellent specificity(99-100%) (10, 11), but yield false positives for several NTM due
to the homology of the gene sequence of the amplification site.
For example, TRCRapid M. TB (Tosoh Bioscience, Tokyo,
Japan) utilizing a transcription-reverse transcription concerted(TRC) method that allows rapid detection of the target RNA
yields false positives for several NTM, including Mycobacterium
shinjukuense (12-21). If NAAT is positive in a suspected TB patient but the subsequent clinical course is inconsistent with TB,
the isolate should be identified by the newly developed matrix-assisted laser desorption ionization-time of flight mass spectrometry or sequence analysis (22). False-positive reactions in MTB
NAATs may occur or have already occurred for unidentified
NTM species without being noticed.

Microbial substitution
Most of the MAC or Mycobacterium abscessus complex (MABC)
isolates re-identified after negative sputum culture conversion
obtained by anti-NTM chemotherapy are the result of reinfections with mycobacteria of different genotypes (23, 24). Furthermore, in the Japanese 2014 survey, the incidence rate of MABC
disease increased five-fold in 7 years and microbial substitutionof MAC to MABC is regarded as one of the reasons (1). MABC
is classified into M. abscessus ssp. abscessus, M. abscessus ssp.
bolletii and M. abscessus ssp. massilience. The ribosomal methyltransferase gene erm (41) confers inducible macrolide resistance(susceptible on day 3 but resistant on day 14 of DST) in M. abscessus ssp. abscessus and bolletii. However M. abscessus ssp. massiliense
is susceptible to clarithromycin even after prolonged incubation
because its erm (41) does not work (24-27). In Japan, the rapidly
growing mycobacteria identification kit using nucleic acid chromatography (KANEKA Corporation, Osaka, Japan) has made it
possible to evaluate MABC subspecies and the erm (41) genotype
in clinical practice. Management of NTM disease requires regular assessment of microbial substitution and reconsideration oftreatment plans.

Abnormal radiological manifestations caused by NTM : Not what
it seems
PNTMD generally presents as bronchiectasis with clusteredcentrilobular nodules (nodular bronchiectatic disease) or upper-lobe cavitary lesions (fibrocavitary disease). However, itoccasionally develops as unexpected lesions.
1. Pneumonia-like shadows
The clinical manifestations of pulmonary mycobacterial
diseases are affected by the immunological background of thehost. For example, significant differences have been reported inchest radiographic and computed tomography (CT) findings of
TB depending on the status of human immunodeficiency virus(HIV) infection and CD4 T cells (28, 29). TB can develop in theearly stage of HIV infection, but NTM disease usually develops
in the late stage (30, 31). Therefore, in HIV-positive patientswith NTM disease, granulomas are not sufficiently formed andexudative lesions become predominant (32). On the other hand,
rapidly progressive pulmonary consolidation due to granulomatous

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inflammation in a patient with PNTMD without immunodeficiency was reported and similar shadows have been found inpatients with rheumatoid arthritis (33-34). In such cases, anexcessive immune response is assumed to be the principal pathological condition and steroid therapy is usually effective (33-34).
2. Miliary pulmonary opacities
A miliary pattern, randomly distributed nodular opacities,
on chest radiographs is generally caused by a systemic disordersuch as hematogenous spread of infection or cancer, and sarcoidosis. TB is a well-known infectious disease that can present witha miliary pattern (35), but NTM disease may also exhibit thesame pattern. In an autopsy-based study, a miliary pattern was
found in cases of disseminated NTM disease with pulmonary
involvement, but not in cases of PNTMD alone (36).
However, miliary opacities are known to be observed in patients with hypersensitivity pneumonitis (HP), or extrinsic
allergic alveolitis, and inhalation of aerosols containing NTM(mainly MAC) can induce a similar clinical presentation. Hot
tub lung (HTL) is a typical disease of this condition and pathologically a granulomatous lung disease (37-39). Like HP, HTL
shows apparent improvement either spontaneously or in response to glucocorticoid therapy after avoiding exposure to thepathogen without anti-NTM chemotherapy (39). The fact thatbacillus Calmette-Guerin (BCG) immunotherapy for bladdercancer sometimes induces systemic granulomatous inflammation supports the hypothesis that HTL is an allergic reaction
rather than an infection (40, 41). In addition, the possibility ofendobronchial spread of NTM (M. xenopi) was reported in an
immunocompromised patient (42).
3. Large pulmonary solitary mass
NTM, especially MAC, infections sometimes cause solitary
pulmonary nodules (SPN) (43). In Japan, the proportion of M.
intracellulare cases is high in the southwestern region (44), but
SPN are mainly due to M. avium infections. SPN in patients with
NTM infection are less likely to cause satellite lesions and calcification than those in patients with MTB infection. Therefore,
this type of disease may not be diagnosed until surgical resection is performed for suspected lung cancer (43). In addition,
granulomas and expanded bronchi with purulent exudate canaggregate together to form a large mass. We previously reported
a lobulated mass with marked 18-fluorodeoxyglucose (FDG)
uptake, mimicking pulmonary mucinous cystadenocarcinoma
due to Mycobacterium kansasii infection (45). As the presentationsof PNTMD are protean, NTM infection should not be excluded
from the differential diagnosis of pulmonary disease simply
based on radiological manifestations alone.

FEATURES OF EXTRAPULMONARY NTM DISEASES THAT ARE DIFFERENT FROM THE CORRESPONDING TUBERCULOUS DISEASESAs MTB survives only in humans and exhibits aerial transmission, it is not directly transmitted into the extrapulmonaryorgans from outside of the body. During primary infection,
hematogenous and lymphatic spread of MTB to extrapulmonary organs occurs before adaptive T-cell immunity is firmly
established. There are two presentations : early-onset following
primary infection and endogenous recurrence from long-surviving MTB in microgranulomatous lesions (46). However, NTM
residues in natural environments (soil and water) and can transmit through the skin, gastrointestinal tract, and sharps injuries
to form extrapulmonary lesions.

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T. Shinohara, et al. Varying clinical presentations of NTM disease

Pleurisy
Tuberculous pleurisy that follows primary infection (primary
TB pleurisy) is the most common extrapulmonary TB in Japan,
and its pathogenesis is considered to be a delayed-type allergic
reaction to TB antigens in the pleural cavity (47). Multiple cytokines released mainly from immune cells increase the permeability of the pleural capillaries and cause pleural effusion (48,49). This condition can resolve spontaneously, but recurrence
was observed in approximately half of untreated cases resulting in serious presentation (50, 51). However, in asymptomaticpatients with pleural thickening suspected to be caused byprimary TB pleurisy, antituberculous chemotherapy is usually
not administered. We previously reported the usefulness of FDG
positron emission tomography / CT evaluation in such a case (52).
On the other hand, primary NTM pleurisy (i.e., without distinct pulmonary involvement) is rare, probably because NTM
are environmental mycobacteria inducing desensitization inhosts before its infection (53). NTM pleurisy may be caused
by a direct extension of infection from pulmonary lesions into
the pleural cavity and is often intractable (54-56). Endoscopic
examination to diagnose PNTMD was reported to cause NTM
pleuritis with pneumothorax probably due to the rupture of a
subpleural lesion during the procedure (20, 57). Recently, Furuuchi et al. reported a case of PNTMD with pleural effusion,suggesting that evaluation of pleural fluid anti-GPL-core IgA
antibody can be a supplementary diagnostic method for the pleural involvement of MAC (58).

Vertebral osteomyelitis
Vertebral osteomyelitis (VO) is now an uncommon clinical presentation of TB, but tuberculous VO was reported to be increasing in the elderly. Patients with bone and joint TB usually have
few typical symptoms and inflammatory markers in patientsare often not elevated. In addition, age-related changes in thevertebra, such as spinal joint deformities and osteoporosis, canaffect radiological findings, leading to oversights or delays in the
diagnosis of tuberculous VO (59).
NTM also cause VO, with about half of the cases occurringin otherwise healthy patients (60-64). Blunt-force trauma wasreported to be a risk factor for VO due to mycobacterial infection,and it is hypothesized that macrophages which have phagocytosed NTM migrate to the injury site for tissue restoration but
release the pathogen resulting in the development of VO (62). An
interesting case of M. abscessus ssp. abscessus disease was recently
reported, which was initially diagnosed as primary pleurisy, butlater turned out to be disease progression from VO (65). The
major pathogen of VO, including cases with exudative pleural
effusion, is Staphylococcus aureus (66, 67), but NTM infection
should be considered, especially in patients with a history of
pre-disposing trauma.

Disseminated mycobacterial disease
Disseminated TB is defined as the hematogenous spread of tuberculous infection involving multiple noncontiguous sites (35).
Miliary TB is a term that refers to miliary granulomas under
the same conditions generally with innumerable tiny spots on achest radiograph (68).
Disseminated NTM disease has been observed in adults withadvanced HIV infection and in cases of severe cellular immune
dysfunction caused by immunosuppressive therapy such as after
hematopoietic stem cell and organ transplantation (30, 31, 69).
In recent years, neutralizing anti-interferon-γ autoantibody
has received a great deal of attention as a new etiology of thiscondition (70-72). It should be noted that the main primary siteof transmission of disseminated MAC (mainly M. avium) diseaseis the intestinal mucosa and this condition does not necessarily
have a preceding lung lesion (73). Blood cultures play an important role in the diagnosis (74) and rapidly growing mycobacteria
may be detected in commonly used aerobic culture bottles. However, BACTEC Myco / F Lytic culture vials are more suitable forthe detection of mycobacterium, especially for slowly growing
species, including MAC (75). NTM can also be the causative
pathogens of catheter-related bloodstream infections (76).

MYCOBACTERIAL DISEASES ASSOSCIATED WITH
IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)
IRIS is a condition noted in some cases of rapid reconstructionor activation of immune function, which increases the immunoinflammatory response to antigens mainly derived frommicroorganisms. It typically causes the development of a newopportunistic infection (unmasking IRIS) or paradoxical clinicalexacerbation of a pre-existing infection (paradoxical IRIS) (77).
Mycobacterial diseases in representative clinical settings of
IRIS are described below.

Introduction of antiretroviral therapy (ART)
Paradoxical exacerbation of existing TB during antituberculous chemotherapy was observed in 36% of HIV-positive patients
who were additionally treated using ART. The median durationof antituberculous chemotherapy before the onset of paradoxical
TB-IRIS was 8 weeks (interquartile range 5.5-11.5 weeks),
whereas the median duration of ART was only 4 weeks (interquartile range 2-10 weeks). In addition to the exacerbation of thepreceding lesions, new lesions may develop in extrapulmonaryorgans, including the central nervous system (78, 79). In thissetting, NTM disease is often recognized as unmasking IRIS
and superficial lymphadenitis is common. Unlike disseminated
NTM disease, lesions may be localized and the positive rate on
blood culture is low (79).

Discontinuation of TNF inhibitors and immunosuppressive drugs
Tumor necrosis factor (TNF)-α is required for the formationand maintenance of granuloma, which confine microbial pathogens difficult to eradicate. Therefore, administration of TNF
inhibitors to patients with autoimmune diseases, such as rheumatoid arthritis, can induce granulomatous infections, including
activation of latent TB (80, 81). Discontinuation of anti-TNF
therapy at the onset of TB can cause paradoxical exacerbation(82). According to the Japanese guidelines, if the susceptibilityof MTB to anti-TB drugs is known and TNF inhibitors can besafely administered, continuation of the treatment using a biological product during antituberclous chemotherapy should beconsidered (83).
Regarding NTM diseases associated with anti-TNF therapy,
the majority of patients were administrated either corticosteroids or methotrexate at the same time, and extrapulmonary
lesions were frequently observed (84). The paradoxical exacerbation of NTM diseases in patients with autoimmune diseases
while undergoing dose reduction, or after the discontinuationof TNF inhibitors or immunosuppressive drugs has also beenreported (85-87). In general, NTM disease is refractory to treatment, making it difficult to notice the paradoxical exacerbation.
However, in the above cases, persistent infection with NTM was
excluded by AFB tests. Moreover, the introduction of steroid
therapy or increase in the dose of glucocorticoid and immunosuppressive drug was effective.

The Journal of Medical Investigation Vol. 68 August 2021
Introduction of immune checkpoint inhibitors (ICIs)
The development of a new opportunistic infection during ICI
therapy has become a concern and many TB cases were considered to be unmasking IRIS. Therefore, confirmation of a negative IGRA result prior to ICI administration may be beneficial,similar to before the administration of TNF inhibitors (88). Approximately half of the cases of unmasking TB during ICI therapy were detected before the onset of subjective symptoms by CT
performed for the purpose of evaluation of ICI therapy against
malignancy (89). The paradoxical exacerbation of existing TB
during nivolumab therapy was also reported in a lung cancer
patient (90). Regarding NTM disease during ICI therapy, there
are only a few reported cases from Japan. Nodular bronchiectatic disease developed in advanced lung cancer patients previously
treated using cytotoxic chemotherapy and thoracic radiotherapy(91). Conversely, there was a case in which the existing pulmonary M. abscessus ssp. massilience disease was improved by ICI
therapy for advanced lung cancer (92). The accumulation of casesof NTM disease in this setting is necessary in order to improvethe management of ICI-induced immune-mediated events.

Recovery from immunosuppression by treatment for the underlying
diseaseParadoxical clinical exacerbation of TB has been recognized,
usually after initial improvement, in otherwise healthy patients
receiving antituberculous chemotherapy, and is referred to as
a paradoxical response or paradoxical reaction (PR) (93). Thisphenomenon may be attributed to an excessive immune response
to massive antigen release from dying MTB coincided withrecovery from TB-induced immunosuppression. In general, theduration of antituberculous chemotherapy before paradoxicalexacerbation is longer in HIV-negative patients than in HIV-positive patients on ART (94).
Several cases of PR in otherwise healthy patients treated for
NTM have also been reported, among which exacerbation ofexisting lesions and the development of new lesions were noted
after negative conversion of the sputum AFB smear results
without redetection of NTM (95, 96). These lesions gradually
improved without changing the chemotherapy regimen.

Recovery from an immunosuppressive condition during pregnancy
Pregnancy is regarded as an immunosuppressive condition
to maintain fetal tolerance and the Th1 response recovers rapidly from the suppressed state during the postpartum period
resulting in the development of new infections including TB(unmasking IRIS) (97, 98). In postpartum TB cases, the frequencies of extrapulmonary and central nervous system involvement
were reported to be approximately 90 and 70%, respectively.
The mortality rate and frequency of sequelae were 38 and 14%,respectively (99). Postpartum tuberculosis may progress to PR
without initial improvement on the same IRIS spectrum (100).
To the best of our knowledge, there are no reports of postpartum
PNTMD. However, many cases of postcesarean section wound
infection caused by MABC have been reported, although the
involvement of immune reconstitution has not been discussed(101, 102).

CONCLUSIONSIn the diagnosis and treatment of pulmonary mycobacterial
disease, it is important to confirm that there is no discrepancy
between the clinical course and the results of AFB tests. If necessary, new and / or existing samples must be examined to confirm the mycobacterial species. As the presentations of PNTMD

223

are protean, NTM infection should not be excluded from thedifferential diagnosis of pulmonary disease simply based onradiological manifestations alone. The development of extrapulmonary NTM diseases is different from that of corresponding
tuberculous diseases because NTM are environmental mycobacteria that can transmit through the skin, gastrointestinal tractand sharps injuries to form extrapulmonary lesions. In addition,
noninvasive trauma may be a risk factor for VO due to NTM
infection. Moreover, it is necessary to pay sufficient attention
to the immune function and its modifiers. As an opportunistic
infection, NTM disease usually develops with more advanced
immunosuppression than TB and is more likely to be disseminated. On the other hand, NTM disease associated with IRIS isless common and unmasking disease is often localized comparedwith TB. The paradoxical exacerbation of NTM disease as IRIS
is usually responsive to the increase in immunosuppression.

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