Clinical Analysis of Pulmonary Nontuberculous Mycobacterial Disease Diagnosed as Coincidental Pulmonary Infection Due to <i>Mycobacterium</i> Species*

doi:10.4236/ojrd.2013.32016

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Open Journal of Respiratory Diseases, 2013, 3, 107-112

http://dx.doi.org/10.4236/ojrd.2013.32016 Published Online May 2013 (http://www.scirp.org/journal/ojrd)

Clinical Analysis of Pulmonary Nontuberculous

Mycobacterial Disease Diagnosed as Coincidental

Pulmonary Infection Due to Mycobacterium Species*

Yoshihiro Kobashi#, Keiji Mouri, Yasushi Obase, Shigeki Kato, Mikio Oka

Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Japan

Email: #[email protected]

Received April 3, 2013; revised April 28, 2013; accepted May 8, 2013

cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Objectives: We analyzed the clinical characteristics of patients with pulmonary mycobacterial disease diagnosed as

coincidental pulmonary infection due to Mycobacterium species. Materials and Methods: One hundred sixty patients

satisfied the diagnostic criteria of nontuberculous mycobacterial disease proposed by American Thoracic Society during

the last seven years. Six patients (3.8%) were coincidental pulmonary infection due to two Mycobacterium species. We

investigated the background, laboratory findings, microbiological findings, radiological findings, treatment and progno-

sis. Results: There were six patients, 3 males and 3 females, with a mean age of 71.7 years. The causative microorgan-

isms of coincidental pulmonary infection consisted of Mycobacterium avium + Mycobacterium intracellulare in two

patients, Mycobacterium avium + Mycobacterium kansasii in one, Mycobacterium intracellulare + Mycobacterium che-

lonae in one, Mycobacterium intracellulare + Mycobacterium abscessus in one, and Mycobacterium intracellulare +

Mycobacterium tuberculosis in one. Regarding the radiological findings, the distribution of the lesion was frequently

shown in both the right middle and left lingula lobes, but the extent of the lesion was limited within the unilateral lung

field. Centrilobular small nodules with bronchiectasis were recognized in all patients and cavities or infiltration shad-

ows were recognized in half of them on chest computed tomography. A definite diagnosis was obtained by bronchoal-

veolar lavage fluid in four patients and expectorated sputum in two. Combined chemotherapy was performed for two

patients and that for pulmonary tuberculosis in one. Conclusions: Coincidental pulmonary infection due to Myco-

bactterium species occurred at a low percentage. Although most patients were elderly with underlying disease and

clinical features were compatible with pulmonary Mycobacterium a vium complex disease, the prognosis was compara-

tively good with and without treatment.

Keywords: Coincidental Pulmonary Infection; Mycobacterium Species

1. Introduction

Since the American Thoracic Society (ATS) proposed

the diagnostic guidelines of pulmonary nontuberculous

mycobacterial (NTM) disease in 2007 [1], the number of

patients with pulmonary NTM disease has been increas-

ing in Japan [2]. Of many causative microorganisms of

pulmonary NTM disease, Mycobacterium avium is the

most common pathogen, Mycobacterium intracellulare is

the second, and Mycobacterium kansasii is the third one

in Japan. Among the microbiological diagnostic criteria

of pulmonary NTM disease, if positive culture results

from at least two separate expectorated sputum samples

or positive culture results from at least one bronchial

wash or lavage are obtained, we can confirm a definite

diagnosis of pulmonary NTM disease in combination

with clinical findings.

Recently, because bronchoscopy has been frequently

performed to obtain a definite diagnosis of pulmonary

NTM disease and its diagnostic usefulness was reported

[3,4], we sometimes discover coincidental pulmonary

infection due to Mycobacterium species. There are few

reports about the clinical characteristics of coincidental

pulmonary infection due to Mycobacterium species as far

as we investigated. Therefore, we clarified the clinical

characteristics of patients with coincidental pulmonary

infection due to Mycobacterium species during the last

seven years in this study.

*The authors declare that they have no conflict of interest (COI).

#Corresponding author.

Y. KOBASHI ET AL.

108

2. Materials and Methods

This study was approved by the institutional review

board (Ethical Committee of Kawasaki Medical School).

Informed consent from each patient was not required

because all data were collected retrospectively. We se-

lected one hundred and sixty patients who satisfied the

diagnostic criteria of NTM disease proposed by ATS [5]

in our hospital between January 2005 and December

2011. Among these patients, six patients (3.8%) had co-

incidental pulmonary infection due to two Mycobacte-

rium species. We investigated the backgrounds, labora-

tory findings, microbiological findings, radiological find-

ings, diagnostic methods, treatment and prognosis of

these patients and the remaining patients with pulmonary

NTM disease (154 patients) in this study.

All data from patients were drawn from charts, which

included age, sex, smoking history and past medical his-

tory. Laboratory findings such as total protein or albumin

showing nutritional condition purified protein derivatives

(PPD) or QuantiFERON (QFT) and microbiological find-

ings such as causative microorganisms or drug sensi-

tivity tests using the Broth MIC method (Kyokuto Phar-

maceutical Industrial Co. Ltd.), as well as the results of

smear and culture tests for acid-fast bacilli, were re-

viewed. Radiological findings, such as portion, extension

of lesion 1) within one-third of the unilateral lung field; 2)

within the unilateral lung field; 3) over the unilateral lung

field) for pulmonary NTM disease, bronchiectatic change,

cavity, centrilobular small nodules, and infiltration shad-

ows, were also reviewed. All radiological findings were

evaluated on computed tomography (CT) scans of the

chest by one pulmologist and one radiologist. In terms of

treatment, the medication for pulmonary NTM disease

was reviewed. Long-term follow-up was evaluated for

these patients to investigate the prognosis.

3. Results

The clinical findings of the patients with coincidental

pulmonary infection due to Mycobacterium species are

shown in Table 1. Six patients (3.8%) had coincidental

pulmonary infection due to two Mycobacterium species,

including Mycobacterium avium complex (MAC). The

mean age of the six patients was 71.7 years and there

were three males and three females. Two patients had a

smoking history. All patients had underlying diseases

and one of six patients received immunosuppressive

treatment.

Regarding the laboratory findings, nutritional condi-

tions such as total protein or albumin were preserved

except in one patient. PPD was positive for two patients

tested and QFT was negative for all five patients tested.

The causative microorganisms in patients with coinci-

dental pulmonary infection due to Mycobacterium spe-

cies consisted of Mycobacterium avium + Mycobacte-

rium intracellulare in 2 patients, Mycobacterium avium +

Mycobacterium kansasii in 1, Mycobacterium intracellu-

Table 1. Clinical findings of the patients with coincidental pulmonar y infe c tion due to Mycobacterium species.

Laboratory findings Drug-sensitivity test

Case Age Sex Smoking

history

Past

history TP

(g/dl)

Alb

(g/dl) PPD QFT

(ZU/l)

Causative

microorganisms SMEBKMINH RFP LVFX CAMTMAMK

1 61 M (+)

Bronchial

asthma

Gastric ulcer

Glaucoma

7.3 4.6 00

10 10



0.21

M. avium

M. kansasii

>128

N.D.

>32

>16

2 68 F (−) Breast

Ca(ope) 6.7 4.1 N.D. <0.05

M. avium

M. intracellulare

>128

128

>32

>16

3 72 F (−) Gastric

Ca(ope) 8 3.7 N.D. <0.05

M. intracellulare

M. chelonae

>128

>32

0.5

0.125

>16

4 84 M (−)

Gastric

Ca(ope)

Unstable

angina

7.9 4.1 00

20 15



<0.05

M. intracellulare

M. abscessus

>128

>32

0.5

>16

5 70 F (−)

RA(Steroid)

Basedow

disease

6.4↓ 3.4↓ N.D. N.D.

M. tuberculosis

M. intracellulare

2.5

0.25 2 0.25 44

6 75 M (+) COPD 7 4 N.D. <0.05

M. avium

M. intracellulare

>128

N.D.

0.125

0.5

>16

TP: Total protein; Alb: Albumin; PPD: Purified protein delivatives; QFT: QuantiFERON; SM: Streptomycin; EB: Ethambutol; KM: Kanamycin; INH: Isoni-

azid; RFP: Rifampicin; LVFX: Levofloxacin; CAM: Clarithromycin; TH: Thionamide; AMK: Amikacin; RA: Rheumatoid arthritis; COPD: Chronic obstruc-

ive pulmonary disease. t

Y. KOBASHI ET AL. 109

lare + Mycobacterium chelonae in 1, Mycobacterium

intracellulare + Mycobacterium abscessus in 1, and My-

cobacterium tuberculosis + Mycobacterium intracellu-

lare in 1, respectively. The results of drug sensitivity

tests for several antibiotics are shown in Table 1. Al-

though the minimum inhibitory concentration (MIC)

showed higher concentrations of most antibiotics for

Mycobacterium kansasii and Mycobacterium abscessus,

it was preserved at lower concentrations of clarithromy-

cin (CAM) for isolated MAC in most patients. The diag-

nostic methods used bronchoscopic specimens in four

patients and expectorated sputum in two.

Concerning the radiological findings (Table 2), lesions

due to pulmonary NTM disease existed within the uni-

lateral lung field and bilaterally in all patients. All pa-

tients had centrilobular small nodules with bronchiectasis

and three of six patients showed multiple cavitary lesions

or infiltration shadows. These radiological findings re-

sembled those of pulmonary MAC disease.

Anti-mycobacterium species treatment was prescribed

for three patients after the diagnosis of pulmonary my-

cobacterial disease. The clinical effect was good for these

three patients with an improvement in clinical symptoms

and radiological findings. There were no complications

with pulmonary NTM disease and the prognosis was

comparatively good (all patients survived from one to

seven years after a definite diagnosis).

The clinical findings of the patients with the remaining

patients with pulmonary NTM disease (154 patients) are

shown in Table 3. The mean age of these patients were

younger and the frequency of patients with underlying

disease was lower compared to those with coincidental

pulmonary infection. The causative microorganisms in

the remaining patients with pulmonary NTM disease

consisted of M. avium in 73 patients, M. intacellulare in

60, M. kansasii in 14, and others in 7, respectively. Con-

cerning the treatment, combined chemotherapy including

antituberculous drugs was performed for half of these

patients. The mortality rate was comparatively low and

most of these patients died of other complications or un-

derlying diseases.

4. Discussion

Since bronchoscopy has been frequently performed to

obtain a definite diagnosis of pulmonary NTM disease,

the number of patients with this disease has been in-

creasing and the usefulness of bronchoscopy has been

reported [3,4]. In this study, the frequency of coinciden-

tal infection due to Mycobacterium species was a low

percentage (3.8%: 6/160) and two species including

MAC were identified in all patients. In a previous report,

Jarand et al. indicated that over half of patients with My-

cobacterium abscessus pulmonary disease (55%) had

coexistent, or a history of, pulmonary MAC disease [5].

They investigated the frequency of only coincident pul-

monary infection due to both Mycobacterium abscessus

and MAC and there are few epidemiological studies on

coincidental pulmonary infection due to different several

Mycobacterium species.

Regarding the background of patients with coinciden-

tal pulmonary infection due to Mycobacterium species,

Table 2. Clinical findings of the patients with coincidental pulmonar y infe c tion due to Mycobacterium species.

Radiological findings

Case

Portion Extent of

lesion※ Cavity Bronchiectatic

change

Centriliobular

small nodules

Infiltration

shadow

Diagnostic

methods Treatment Clinical

effect Complication Prognosis

1 Bilateral 2 (+) (+) (+) (+)

BALF

(Smear(+),

Culture(+))

RFP + EB + CAM

+ S

(6 months)

Good (−) Survival

(1 year)

2 Bilateral 1 (−) (+) (+) (−)

BALF

(Smear(−),

Culture(+))

(−) (−) Survival

(7 years)

3 Bilateral 2 (+) (+) (+) (+)

Sputum

(Smear(+),

Culture(+)

CAM + EB + SM +

LVFX

(1 year)

Good (−) Survival

(3 years)

4 Bilateral 2 (+) (+) (+) (+)

BALF

(Smear(+),

Culture(+))

(−) (−) Survival

(3 years)

5 Bilateral 2 (−) (+) (+) (−)

Sputum

(Smear(+),

Culture(+))

INH + RFP + EB

+ PZA (6 months) Good (−) Survival

(2 years)

6 Bilateral 2 (−) (+) (+) (−)

BALF

(Smear(+),

Culture(+))

(−) (−) Survival

(1 year)

ALF: Bronchoalveolar lavage fluid; ※1: Within one-third of the unilateral lung field; 2: Within the unilateral lung field; 3: Over the unilateral lung field.

Y. KOBASHI ET AL.

110

Table 3. Clinical findings of the patients with pulmonary

NTM disease excluding the patients with coincidental pul-

monary infection due to Mycobacterium species (154 cases).

Age (Mean ± S.D., years) 68.5 ± 10.4

Sex (Male:Female ) 61:93

Smoking history (+) 70 (45%)

Underlying disease (+) 108 (70%)

46 (30%)

Respiratory disease

Non-respiratory disease







62 (40%)

Causativemicroorganisms

M. avium 73 (47%)

M. intracellulare 60 (39%)

M. kansasii 14 (9%)

Others 7 (5%)

Radiological findings

109 (71%)

Bilateral

Portion Unilateral







45 (29%)

60 (39%)

78 (51%)

Extension #2







16 (10%)

Cavity 95 (62%)

Bronchiectatic change 137 (89%)

Diagnostic methods

Sputum 72 (47%)

BALF 71 (46%)

Others 11 (4%)

Treatment

Combined chemotherapy 80 (52%)

Surgical operation 6 (4%)

Prognosis

Died 18 (12%)

BALF: Bronchoalvelar lavage fluid;

1:Within one-third of unilateral lung field

#2:Within unilateral lung field

3:Over unilateral lung field







elderly patients with underlying diseases such as respira-

tory diseases or malignancies were common, as in pre-

vious reports [6,7], but nutritional conditions were pre-

served except in one case.

The radiological findings of 6 patients with pulmonary

MAC disease such as centrilubular small nodules with

bronchiectatic changes mainly in the right middle lobe or

left lingula segment were a common characteristic. Ra-

diological abnormalities of pulmonary MAC disease

have been classified into the following five patterns on

the basis of chest CT: nodular and bronchiectatic disease,

fibrocavitary disease, solitary nodule disease, hypersen-

sitivity disease, and disseminated disease [1]. Of the five

patterns, nodular and bronchiectatic disease was the most

frequent and fibrocavitary disease was the second most

frequent in previous reports. All patients had MAC as

causative microorganisms of coincidental pulmonary

infection in this study. The radiological findings of My-

cobacterium abscessus or Mycobacterium chelonae pul-

monary disease have been said to resemble those of

MAC pulmonary disease in previous reports [1,5,8]. On

the other hand, the radiological findings of Mycobacte-

rium kansasii pulmonary disease or pulmonary tubercu-

losis had characteristic thin or thick cavities located in

the apical segment [9]. We think that it is difficult to

suggest the causative microorganism from the radiologi-

cal findings in patients with coincidental pulmonary in-

fection due to Mycobacterium species based on this study.

We followed-up patients with pulmonary MAC disease,

and Mycobacterium tuberculosis were also isolated si-

multaneously from one patient (Case 5). She was receiv-

ing immunosuppressive treatment (corticosteroid drugs)

and was in a poor nutritional condition. Because new

lesion appeared in the bilateral upper lobe on periodical

chest CT (Figure 1), the attending physician performed

an acid-fast bacilli examination and, finally, Mycobacte-

rium tuberculosis was detected. Physicians must be care-

ful when treating immunocompromised patients compli-

cated with pulmonary tuberculosis.

(a)

(b)

Figure 1. (Case 5) Coincidental pulmonary infection due to

Mycobacterium intracellulare and Mycobacterium tuberculo-

sis. New lesion with centrilobular small nodules on chest CT

appea r ed i n th e b i l a tera l u p p e r l obe . ( a ) 2 009. 10; (b) 2010.11.

Y. KOBASHI ET AL. 111

Concerning the diagnostic methods, the bronchoscopic

procedure is important to acquire accurate information

about coincidental pulmonary infection due to Mycobac-

terium species. In this study, four of six patients were

given an accurate diagnosis using bronchoalveolar lavage

fluid (BALF). Although bronchoscopy is an invasive

technique, we think it is necessary to consider a differen-

tial diagnosis of pulmonary NTM disease.

Regarding the selection of treatment, ATS/IDSA pro-

posed a guideline for treatment of pulmonary NTM dis-

ease in 2007 [1]. The therapy for pulmonary MAC dis-

ease was recommended as combined chemotherapy in-

cluding a macrolide (clarithromycin (CAM) or azithro-

mycin (AZM)), ethambutol (EB), rifampicin (RFP) ±

aminoglycoside depending on disease status and/or se-

verity. On the other hand, therapy for pulmonary Myco-

bacterium abscessus or Mycobacterium chelonae disease

was recommended as combined chemotherapy consisting

of a macrolide, aminoglycoside, imipenem and cefoxitin

and that for pulmonary Mycobacterium kansasii disease

was combined chemotherapy including isoniazid (INH),

RFP and EB. There is a little difference in the treatment

between Mycobacterium species. Therefore, it is impor-

tant to identify the species in NTM. However, the clinical

effect of combined chemotherapy for pulmonary NTM

disease except for pulmonary Mycobacterium kansasii

disease was not good (clinical symptoms and/or abnor-

mal radiological findings) [10]. There are no guidelines

for initiating or ending treatment or the adaptation of

treatment for elderly patients. Consequently, combined

chemotherapy was performed for three of six patients

because there were mainly elderly patients in this study;

multi-drug chemotherapy including CAM for two pa-

tients and antituberculous treatment for Mycobacterium

tuberculosis for one. The clinical effect due to combined

chemotherapy was good and the prognosis was also good

despite their general condition. We do not think there

was a relationship between coincidental pulmonary in-

fection and clinical effect or prognosis of the subjects in

this study.

There are a few limitations in this study. Firstly, there

were only a few patients with coincidental pulmonary

infection due to Mycobacterium species among patients

with pulmonary mycobacterial disease in one hospital in

a restricted area, so we need to perform a large-scale

study including several hospitals in Japan to get an accu-

rate of coincidental mycobacterial infection. Secondly,

the rate of coincidental mycobacterial infection was lower

than in other reports [5]. This is because the diagnostic

accuracy of the acid-fast bacilli culture was poor in our

laboratory when patients with coincidental infection due

to Mycobacterium species were tested.

In conclusion, the rate of coincidental pulmonary in-

fection due to Mycobacterium species was a low per-

centage and clinical characteristics were similar to those

of pulmonary MAC disease mainly on the radiological

findings. Although most patients were elderly with un-

derlying diseases, the clinical effect and prognosis were

comparatively good.

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