Title

Author(s)

Use of fibreoptic bronchoscopy in diagnosing sputum smearnegative pulmonary tuberculosis

Kwan, Hoi-yee;

Citation

Issued Date

URL

Rights

2010

http://hdl.handle.net/10722/133487

Creative Commons: Attribution 3.0 Hong Kong License

Use of fibreoptic bronchoscopy in diagnosing sputum smear-negative

pulmonary tuberculosis

By

Dr Kwan Hoi Yee

2005941601
MBChB, MRCP(UK), MPH(HK)

This work is submitted to

Faculty of Medicine of The University of Hong Kong
In partial fulfillment of the requirements for
The Postgraduate Diploma in Infectious Diseases, PDipID (HK)

Date: 30.6.2010

Supervisor: Dr Susanna Lau

Declaration

I, Kwan Hoi Yee, declare that this dissertation represents my own work and that it has
not been submitted to this or other institution in application for a degree, diploma or
any other qualifications.
I, Kwan Hoi Yee, also declare that I have read and understand the guideline on What
is plagiarism? published by The University of Hong Kong (available at
http://www.hku.hk/plagiarism/) and that all parts of this work complies with the
guideline.

Candidate:

Kwan Hoi Yee

Signature:
Date:

30.6.2010

Acknowledgement
I would like to express my heartful gratitude to my supervisor Dr Susanna Lau,
Dr PL Ho and Professor KY Yuen, for the excellent guidance, invaluable comments
and advices that they have given to me throughout the period that I was preparing this
project dissertation. Without their guidance and support, this dissertation would not
have been existed and completed.
Special thanks is given to course secretariat Miss Karis Lam, for the encouraging
e-mails that she has sent and all the helps that she has provided me during the study of
this course.
Last but not least, I would like to take this opportunity to thank my family and
friends, who have given me endless support. Without their help and encouragement, I
would not have been able to complete my project dissertation and this course.

List of abbreviations
AFB

Acid-fast bacilli

AIDS

Acquired immunodeficiency syndrome

BAL

Bronchoalveolar lavage

CT

Computed tomography

CXR

Chest roentgenogram

DOTS

Directly observed treatment short-course

FNAC

Fine-needle aspiration cytology

HIV

Human immunodeficiency virus

HRCT

High resolution computed tomography

MDR-TB

Multidrug-resistant tuberculosis

MTB

Mycobacterium tuberculosis

PCR

Polymerase chain reaction

SSN-TB

Sputum smear-negative pulmonary tuberculosis

TB

Tuberculosis

WHO

World Health Organization

XDR-TB

Extensively drug-resistant tuberculosis

XPTB

Extra-pulmonary tuberculosis

Abstract
Background: Tuberculosis (TB) remains a major health problem worldwide. Rapid
diagnosis helps early commencement of appropriate treatment and infection control,
which is particularly difficult to achieve among sputum smear-negative subjects.
Various diagnostic methods have been employed. The role of different bronchoscopic
sampling techniques remains unclear.
Objectives: To evaluate the value of fibreoptic bronchoscopy in the diagnosis of
pulmonary tuberculosis among sputum smear-negative patients in a peripheral
hospital in Hong Kong.
Methods: Medical records of 22 patients, who have underwent bronchoscopy in the
North District Hospital, Hong Kong, in 2009, and were later diagnosed of having
pulmonary TB, were reviewed. Their demographic data and the results of their
different pulmonary specimens were recorded. The exclusive diagnostic test for TB
for each one of them was identified.
Results:

All

the

22

bronchoscopies

were

performed

as

elective

cases.

Bronchoalveolar lavage (BAL) has been performed in all of them. Positive acid-fast
smear and culture were obtained in three cases (13.6%) and six cases (27.3%)
respectively, which provided the exclusive means of diagnosis for four cases (three
from smear, one from culture). Molecular study from BAL was performed in 14 cases.
5

Among them, five cases got positive results (35.7%). It was the exclusive means of
diagnosis for two cases. Transbronchial lung biopsy (TBLB) has been performed in
19 cases. All of the specimens were sent for histology. Specimens from six cases were
also sent for acid-fast bacilli (AFB) culture. It provided positive results by histology
for five cases (26.3%), which was the exclusive means of diagnosis for two cases.
TBLB AFB culture was positive in three cases, one of them provided the diagnosis
exclusively, while TBLB AFB smear were all negative. The complication rate was
low (4.5%). No fatalities have been reported.
Conclusion: While sputum examination remains the cornerstone in diagnosing
pulmonary TB, fibreoptic bronchoscopy together with various bronchoscopic
sampling techniques served as a useful adjunct to optimize the diagnostic yield,
especially among patients who are sputum smear-negative for AFB.
(Word count: 326)

Background
Tuberculosis (TB) remains a major health problem worldwide.(1, 2) The
occurrence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB
(XDR-TB) adds burden to this major public health issue.(3) Recent estimates revealed
that there were 8.8million new TB cases in 2005, 7.4million of them were in Asia and
sub-Sahara Africa; 1.6million people died of TB, including 195,000 patients
co-infected with the human immunodeficiency virus (HIV).(1) Hong Kong is
classified as a place of intermediate TB burden with good health infrastructure in the
Western Pacific Region.(4) In 2009, the total number of notified cases in Hong Kong
is 5348, at a rate of 76.36 per 100,000.(5)
The cornerstone of rapid diagnosis of pulmonary TB is sputum microscopy,
which is a highly specific and low cost test.(1, 6) The collection of three samples of
self-expectorated sputum on three different days, preferably in the early morning, is
the standard investigation for patients suspected of having pulmonary TB and able to
self-expectorate.(6, 7) However, only approximately one-third of pulmonary TB cases
are smear-positive, whereas the remaining two-thirds are culture-proven.(6)
Mycobacterial cultures take at least six to eight weeks time for confirming the
diagnosis and thereby a valuable time is lost.(1, 8) The prevalence of culture-positive
cases among smear-negative patients was only 52%, despite collecting up to four
sputum specimens before treatment. The sputum smear is less often positive in
7

patients co-infected with human immunodeficiency virus (HIV).(9) Despite best

efforts in collecting sputum, processing, and examination, some patients with active
TB do not produce adequate sputum, while others who produce adequate sputum also
remain smear-negative for reasons that are as yet unknown. (1) In areas with low
transmission of TB, molecular studies found that about 17% of the disease
transmission could be attributed to smear-negative culture-positive index patients. The
figure would probably be much higher in endemic areas. The mortality rate for
smear-negative, culture-positive cases was 14.1% compared with 34.7% observed in
smear-positive patients.(1) The infectiousness of patients with extra-pulmonary
tuberculosis (XPTB) has often been underestimated. Parimon et al. found that chest
roentgenogram (CXR) results, and even computed tomography (CT) of thorax, failed
to reliably differentiate XPTB in patients with or without positive sputum culture
findings. Among the 57 patients from whom sputum was collected by sputum
induction, five (9%) had sputum smears that were positive for acid-fast bacilli (AFB),
while 12 (21%) have sputum cultures positive for Mycobacterium tuberculosis (MTB).
Two out of 24 HIV-negative XPTB patients with normal CXR findings have positive
sputum cultures (8%). The results of sputum AFB smears and cultures may not alter
the management of XPTB cases, but they may change the approach to conducting
contact investigations. Obtaining an adequate specimen sample for AFB culture is
8

important not only for diagnosing TB, but is also necessary to assess drug
susceptibility, especially in this era of MDR-TB and XDR-TB.(2) Early diagnosis
enables prompt initiation of treatment, which in turn helps to improve treatment
outcomes and prognosis, as well as rendering them non-infectious and thereby
interrupts the chain of transmission of TB.(1, 8)
Various methods have been employed to ascertain active TB disease in patients
with suspected sputum smear-negative pulmonary tuberculosis (SSN-TB) (Table 1),
including mathematical modeling for predicting active diseases. Among them,
bronchoscopic procedures have been studied in some details.(1) The utility of
bronchoscopy and the conventional microbiological and histopathological diagnostic
methods in the diagnosis of TB has been evaluated both prospectively and
retrospectively.(1)

On one hand it has been reported to be useful in the confirmation

of the diagnosis of TB, especially in patients with SSN-TB, on the other hand, it is a
costly test and an invasive procedure.(1, 10) The risk of cross-contamination,
especially if the suspect with SSN-TB harbours multidrug-resistant strains of MTB,
should not be overstated.(1) Previous studies have examined the role of bronchial
washings, lavage and transbronchial biopsy for histology in the diagnosis of TB,
while relatively little attention has been paid specifically to the role of transbronchial
lung biopsy culture in this aspect.(10)
9

To further evaluate the contribution of bronchoscopy in the diagnosis of

pulmonary TB in an endemic area, medical records of confirmed pulmonary TB cases
that have undergone bronchoscopy were reviewed. The diagnostic yield of different
pulmonary specimens including sputum, bronchoalveolar lavage (BAL), and
transbronchial lung biopsy, for pulmonary TB were determined. Results were then
compared with similar published studies.

10

Method
At the North District Hospital, a peripheral hospital in Hong Kong, 248 flexible
bronchoscopies have been performed in the medical unit in the year 2009. Subjects
were matched with records from the microbiology laboratory to identify subjects in
whom pulmonary specimens yielded MTB, or that anti-tuberculous treatment has
been commenced empirically which led to symptom improvement clinically or
radiologically. Acid-fast smears of sputum were negative for 22 of them prior to
bronchoscopy. They constituted the study population.
Medical records of the studys patients were reviewed to obtain clinical and
laboratory data. Demographic data including their age, sex, pre-morbid state and their
residence were recorded. Their smoking status was classified as current smokers,
non-smokers who never smoke, and ex-smoker, whom have quitted smoking for more
than one year prior to the studied bronchoscopy. Their past medical histories were
reviewed to identify any risk factor for developing tuberculosis. Based on whether
they have history of tuberculosis or have been taking anti-tuberculous drugs in the
past, they were classified into three different case categories: new case: patients
with active pulmonary TB, who have never been diagnosed of having this disease and
have never received anti-tuberulous drug before; relapse case: patients completed
anti-tuberculous drugs before and were diagnosed of having active pulmonary TB; or
treatment after default: patients who has previously interrupted anti-tuberculous
11

treatment for two consecutive months or more, and were diagnosed of having active
pulmonary TB: Progress notes were reviewed to identify subjects who reported
positive contact history with confirmed pulmonary tuberculosis before the procedure.
Their CXR prior to bronchoscopies were reviewed to assess the extent of disease and
the radiological features. The indications for bronchoscopy, the bronchoscopic
findings, and any procedure related complications were recorded.
Bronchoscopies were performed electively as scheduled in-patient procedures by
either fellows, or trainees in pulmonary medicine under the supervision of
experienced trainers, using standard flexible bronchoscopes (Olympus America Inc;
Melvelle, NY). Before the procedure, either midazolam, pethidine, lignocaine spray
and or or lignocaine gel would be given for sedation. Additional 1% lignocaine would
be instilled topically to the appropriate site of the lower airway during the procedure if
necessary. The use of either one or combinations of these drugs was at the discretion
of the responsible bronchoscopist. Similarly, pulmonary specimens that were sent for
investigations during the procedures, and the sites where they were being saved, were
decided by the responsible endoscopists. BAL speciemens were obtained by wedging
the bronchoscope into a segment of the lung and instilling about 20ml aliquots of
0.9% sterile normal saline. The lavage procedure was repeated for four to five times,
aiming to infuse a total of 100ml per site, and to obtain a minimum of 40% of the
12

volume infused. Transbronchial lung biopsies were done with or without fluoroscopic
guidance. The specimens were then placed in formaldehyde solution for
histopathological examination, and in sterile normal saline for mycobacterial studies.
Bronchial brush cytology was performed on one subject. Acid-fast stains and
Mycobacterial culture were performed according to the standard protocol of the
microbiology laboratory.
Pulmonary specimens were considered to be positive for the diagnosis of
tuberculosis if any bronchoscopic specimens, sputum samples or early morning
gastric aspirates that were saved within one month of the bronchoscopy revealed AFB
on smear, or MTB on culture, or granulomatous inflammation was noted on
histopathologic examination of biopsy specimens. The test was considered to be the
exclusive means of diagnosing pulmonary tuberculosis if it was the first diagnostic
test, or the only positive test for MTB. Additional radiological imaging studies were
ordered based on history, physical findings or abnormal laboratory results. Repeating
bronchoscopy or computerized tomograph (CT) guided transthoracic fine needle
aspiration for cytology by radiologists was suggested to obtain proper tissue diagnosis,
if the first procedure failed to obtain a definitive diagnosis. One subject was referred
to the cardiothoracic surgeons for thoracoscopic lung biopsy. Chest tapping was
performed in one subject who presented with pleural effusion to obtain pleural fluid
13

and pleural biopsy for microbiological and pathological investigations.

Not all of the different bronchoscopic procedures were used in parallel in all
patients. Frequency of use of the different diagnostic procedures and their impact on
the diagnostic yield were therefore analyzed.

14

Results
In the year 2009, bronchoscopy has been performed on 22 patients who were
subsequently diagnosed of having pulmonary tuberculosis. About 77.3% of them (17
patients) were new cases. Five of them (22.7%) got history of pulmonary tuberculosis.
Three patients (13.6%) has received whole course of anti-tuberculous treatment
before and were labeled as relapse case. Two patients (9.1%) have defaulted
anti-tuberculous treatment in the past. (Figure 1)

Among all these 22 patients, 17 (77.3%) of them were male and five of them
were female (22.7%). (Table 2) Most of them were above 70-year-old (10 patients,
45.5%). Only two patients (9.1%) were between the ages of 18 to 30. About 86% of
them (19 patients) were living with their families. Only one of them came from
elderly home (4.5%). Two of them have been living alone (9.1%). More than 90% of
them (20 patients) were independent in their activities of daily living. None of them
has been totally dependent in their basic activities of daily living. Eight of them
(36.4%) were smokers, while three of them (13.6%) have quitted smoking for more
than one year, and seven of them (31.8%) have never smoked before. The smoking
status of four subjects was uncertain because it was not stated in their medical records.
Only one subject reported close contact with a patient with pulmonary tuberculosis
about one month prior to his symptom onset.
15

Among these 22 patients having pulmonary tuberculosis, seven of them got no

definite risk factor for developing the disease. Eight out of the remaining 15 of them
(53.3%) got diabetes mellitus. Three of them have been chronic drinker (20%). One
patient has been receiving long-term steroid for treatment of eczema. One of them got
stomach cancer who refused surgery and has not been taking cytotoxic drug. Other
risk factors reported included lung cancer, chronic renal failure, concomitant infection
with HIV, and general debilitation. (Figure 2)
All of these 22 bronchoscopies were performed in the endoscopy unit as elective
cases. The applications of sedation as pre-med were shown in Table 3. Topical
lignocaine (1%) was applied in all except two cases. The mean volume of topical
lignocaine being used was 12.95ml (standard deviation 5.24ml; range 0-22ml; median
12ml; mode 12ml). The indications of bronchoscopy and the corresponding number of
cases being performed were listed in Figure 3. Bronchoscopies were performed on ten
patients (45.5%) for suspected having pulmonary tuberculosis. Five of them (22.7%)
underwent bronchoscopies for having hemoptysis. Another five of them (22.7%)
underwent bronchoscopies because of having solitary pulmonary lung nodule on their
chest roentgenogram. Other indications included having unresolved pneumonia, and
suspected of having lung cancer (one subject for each). Mucosal lesions were found in
two of them (9.1%). Bronchoscopy found no abnormality in the remaining 20 patients
16

(90.9%) (Figure 4).

Their radiological features on CXR and their extent of disease were shown in
table 4. More than half of them got minimal disease, as the radiological involvement
on chest roentgenogram was less than a single lobe. Two of them got advanced
disease, as both lungs were affected radiologically. Most of them got pulmonary
infiltrates (eight patients, 36.4%), seven of them (31.8%) got pulmonary nodules on
their chest roentgenogram, while five of them (22.7%) got cavitatory lesions. One of
them got miliary disease (4.5%), while another one of them got pleural effusion
(4.5%).
The number of applications of the individual bronchoscopic sampling techniques
and their diagnostic yield in pulmonary tuberculosis were listed in table 5. The
frequencies of individual tests being the exclusive means for diagnosing pulmonary
tuberculosis were shown in figure 5. BAL was the only technique performed in every
bronchoscopy. Positive acid-fast smear was obtained in three cases (13.6%), all of
them were the only tests that provided a positive result. A positive AFB culture was
obtained in six cases (27.3%), one of them was the only technique with a positive
result. Specimens were sent for molecular study in 14 cases (63.6%). Five cases got
positive results (35.7%). It was the exclusive test for diagnosis in two cases (9.1%).
Transbronchial lung biopsy was performed in 19 cases. Adequate samples were saved
17

in all cases. All of the specimens were sent for histology, while specimens from six
cases were sent for acid-fast bacilli culture also. Positive results were obtained from
histology in five cases (26.3%), while two of them were the only tests that were
positive for diagnosis. None of the transbronchial biopsy was positive for acid-fast
bacilli smear, but positive culture was obtained in three cases, and one out of these
three cases was exclusive for the diagnosis of pulmonary tuberculosis.
Bronchial brush cytology was performed in only one case, and it gave a negative
result.
In order to compare the diagnostic yield by different bronchoscopic sampling
techniques and other diagnostic techniques, other investigations that have been
performed in these included patients were also reviewed. At least one sputum
specimen has been sent by all 22 patients for AFB smear and culture. All of them
were smear-negative for acid-fast bacilli, but was subsequently culture positive in ten
cases (45.5%). It was the only positive tests in five cases (22.7%). Early morning
gastric aspirate has been sent by four patients (18.2%). Three specimens have been
sent from each patient in three consecutive days. None of them got positive AFB
smear, but culture was positive in one case (25%), which was also the only positive
test in diagnosing pulmonary tuberculosis for this patient (4.5%).
Other diagnostic tests that has been performed included CT guided transthoracic
18

fine-needle aspiration cytology (two patients, 9.1%), CT of the thorax (two patients,
9.1%), chest tapping to send pleural fluid for AFB culture (one patient, 4.5%), and
thoracoscopic lung biopsy (one patient, 4.5%). All of them were the only technique
that gave positive results for those patients with tests done. One subject got positive
smear for AFB from bronchoalveolar lavage by repeating bronchsocopy in a later
date.
There were no fatalities associated with bronchoscopy. One of them developed
hemorrhage after performing transbronchial lung biopsy which required topical
adrenaline and cold saline to stop the bleeding. (Table 6)
Anti-tuberculous drugs were commenced in 19 cases. Three patients died before
diagnoses were made. Ten patients have their anti-tuberculous treatment commenced
in ward during their index admission. One of them got a positive result during his
follow-up in medical clinic and was then put on treatment. Eight cases (36.4%) were
referred to the chest clinic for starting treatment, after positive culture results were
received in the subsequent dates. (Figure 5)

19

Discussion
TB is a major health problem worldwide, and an important preventable and
treatable cause of death. Early appropriate treatment renders patients with active
pulmonary tuberculosis non-infectious and interrupts the chain of transmission of
TB.(1) Pulmonary damage caused by tuberculosis could be minimized with early
treatment. The duration of chemotherapy to achieve the desired effect also depends on
the extent of the disease at the time of diagnosis, which is particularly important
among immunocompromised patients.(8) Therefore, early detection of the disease is
an important component of TB control.(1, 8) Sputum microscopy is a highly specific
and low-cost test.(1, 11) It is an essential component of the directly observed
treatment short-course (DOTS) strategy of the World Health Organization (WHO).(1)
However, sputum smear is not always positive. Smear negative, culture positive
state has been observed in 22% to 61% of cases. SSN-TB remains a common problem
faced by the clinicians, especially in diagnosing patients with immunosuppressed
states who often present with SSN-TB, such as those having HIV infection and
acquired immunodeficiency syndrome (AIDS). Mycobacterial cultures take at least
six to eight weeks time for confirming the diagnosis and thereby a valuable time is
lost. Several diagnostic methods have been applied to sputum, e.g. sputum PCR,
antigen detection etc. but their yield have not been consistently helpful in the
published literature. The utility of flexible fibreoptic bronchoscopy and the
20

conventional microbiological and histopathological diagnostic methods in the

diagnosis of pulmonary TB has been evaluated both prospectively and retrospectively.
Various bronchoscopic sampling techniques may help in increasing the diagnostic
yield and thus allowing early diagnosis.(1, 8, 12-15)
In this study, all the recruited subjects were SSN-TB. Most of them were elderly
(45.5% older than 70-years-old), living with family (86.4%), and were independent in
their activities of daily living (90.9%). The small number of institutionalized and
debilitated patients being recruited in this study could be accounted for by selection
bias, as bronchoscopies would be offered to patients with relatively good pre-morbid
state. They did represent a group of subjects among which infection control was
especially important, for they were ambulatory and have been living with family,
which could be made possible by early diagnosis and prompt treatment for their active
diseases.
Most of the patients in this study got minimal radiological involvement (59.1%).
The mostly described radiological feature on their chest roentgenogram was
infiltrates (36.4%). In the presence of solitary pulmonary nodule, the diagnostic
yield by flexible bronchoscopy could ranges from 10% to 80%, depending on the size
of the nodule.(16) In individuals with pulmonary infiltrates on their CXR and
whose sputum smears were negative for AFB faced a big problem for diagnosis in
21

clinical practice. BAL has been used with great success as a tool for recovering
pathogenic micro-organisms from the lower respiratory tract. S. Charoenratanakul et
al. reported a diagnostic yield of overall bronchoscopic procedures for tuberculosis of
32.5%, among SSN-TB patients, in whom chest roentgenogram revealed minimal
infiltration.(17)
The fact that only one of the patients in our study reported a positive contact
history, five of them got history of pulmonary TB, while two of them have defaulted
anti-tuberculous treatment before, less than 50% of them got risk factor for
developing pulmonary TB, showing that their history and radiological findings gave
little clue in the diagnosis of pulmonary TB, reflecting the importance of adequate
investigation on patients with respiratory symptom in an endemic area for TB.
All the bronchoscopies were performed as elective cases in the bronchoscopy
suite. The complication rate reported in this study was low, only 4.5%, compared with
the reported complication rate ranges from <1% to 6% world-wide.(18) No fatalities
were reported in this study. The appearance of the bronchial mucosa was seem to be
relatively unhelpful in the diagnosis of pulmonary TB, as more than 90% of patients
got normal findings, despite the fact that bronchoscopy was performed in nearly 50%
of them for suspected pulmonary TB. Thus further bronchoscopic sampling
techniques were necessary to give clinicians additional information for making the
22

diagnosis. However, it has been found that when inflammation was noted on gross
examination of the bronchi, the diagnostic yield of culture and histology by
bronchoscopy would be significantly improved.(11) In fact, fibreoptic bronchoscopy
has been found to be a relatively safe technique with few complications.(11) The
safety with which bronchial brushings and transbronchial biopsy specimens could be
taken through the fibreoptic bronchoscope makes it an attractive method of
investigating patients with radiographic features suggestive of tuberculosis at a stage
in the natural history before the tubercle bacilli are being expectorated.(8)
In our centre, it was a routine practice to collect bronchoalveolar lavage during
the bronchoscopy procedure to send for AFB smear and culture. The diagnostic value
of such a practice has yet been sufficiently studied.(1, 11) Kvale et al detected a high
false negative rate of 65% from the routine culture of bronchial trap for M
tuberculosis.(19) Jett et al reviewed 6879 bronchoscopic studies done over a five-year
period in the 1970s. They have performed 6879 flexible bronchoscopic studies,
among which cultures for mycobacteria were collected in 4120 (60%) of the
procedures. Mycobacterial organisms, typical or atypical, other than Mycobacterium
gordonae were isolated in 70 (1.7%) of the 4120 patients. They concluded the
incidence of positive mycobacterial cultures from bronchoscopy is low. Routine
bronchoscopic cultures for mycobacterial organisms should not be obtained on all
23

patients undergoing bronchoscopy. However, they also found a high degree of

sensitivity from bronchoscopic washings in diagnosing MTB (94%). They suggested
that mycobacterial cultures should be collected at diagnostic bronchoscopy in patients
without an established alternative diagnosis.(14)
So et al. gave different opinions. They reviewed the records of 65 patients with
proven pulmonary TB who had undergone flexible bronchoscopy over a two-year
period. All of them were either sputum smear negative or had no sputum prior to the
procedure. Immediate diagnosis was provided by bronchoscopy in 65% of patients,
while a definitive diagnosis was made in 95% of them. Since it was the exclusive
source for diagnosing pulmonary TB in 12% of patients, they advocated its routine
use during bronchoscopy.(20) Ip et al. reviewed the results of routine bronchial
aspirate culture for mycobacteria in 144 cases of confirmed tuberculosis who have
underwent flexible bronchoscopy. They found that positive bronchial aspirate cultures
were obtained from 82.6% of them, and it was the exclusive means of diagnosis in
44.4%. In about two-thirds of the cases, pulmonary TB was not suspected at the time
of bronchoscopy. They therefore advocated the routine culture of bronchial aspirates
for mycobacteria, especially in areas endemic to tuberculosis.(21)
In this study, although the sensitivity of AFB culture from bronchoalveolar
lavage was lower compared with that of sputum AFB culture (27.3% vs 45.5%), the
24

former was the exclusive diagnostic test in one case (4.5%). The sensitivity of AFB
smear from bronchoalveolar lavage was 13.6%, while that for MTB direct test was
35.7%. These two sampling methods were the only positive tests in three patients and
two patients respectively. Thus bronchoalveolar lavage provided early diagnosis and
treatment in five patients with active pulmonary TB, and provided diagnosis
exclusively in six patients, compared with only five patients by sputum AFB culture
alone. Whether to perform routine culture for MTB in all patients undergoing
bronchoscopy mainly depends on its cost-benefit, and the practice differs in various
centers.(11) In areas with high prevalence of pulmonary TB like Hong Kong, routine
examination of bronchial washings for MTB could be useful, especially important in
detecting cases with atypical presentations of pulmonary TB.(1, 11) It must be
stressed that apart from providing absolute identification of MTB, mycobacterial
culture also allowed drug sensitivity studies, which was particularly important in this
era of MDR-TB and XDR-TB.(22)
How about the role of transbronchial lung biopsy in diagnosing pulmaonry TB?
Stenson et al reviewed medical records of 12 sputum smear-negative patients with
culture-proven pulmonary tuberculosis in the 1980s. They found that bronchoscopic
procedures resulted in an immediate diagnosis in five out of their 12 patients (42%),
but only two of them had a positive culture from their transbronchial lung biopsy and
25

it was not the exclusive source in any of them.(1, 10) They concluded that
transbronchial biopsy culture in suspected cases of pulmonary TB adds little to the
bacteriologic diagnosis otherwise established by culturing prebronchoscopy and
postbronchoscopy sputa and bronchial washings.(10) In the series reported by S
Charoenratanakul et al., the diagnostic yield of transbronchial biopsy histology in
SSN-TB was 17.5%, compared with 15% obtained by bronchoalveolar lavage for
AFB culture. They advocated the role of transbronchial biopsy in early diagnosis and
providing immediate evidence of mycobacterial disease. The author recommended
routine performance of transbronchial biopsy in all cases if possible.(17) Kennedy et
al. compared the diagnostic yield of bronchoscopy in pulmonary TB among
HIV-infected and non-HIV infected patients. They found that the sensitivities of the
acid-fast smear and of mycobacterial culture of bronchoscopic specimens and
postbronchoscopic sputum were similar in patients with or without HIV infection.
Transbronchial biopsy provided incremental diagnostic information not available
from evaluation of sputum or bronchoalveolar lavage fluid, through histopathologic
demonstration of granulomatous inflammation. Cultures of transbronchial biopsies
only provided the exclusive source of MTB in a minority of patients.(23) Miro AM et
al. evaluated the relative diagnostic contribution of sputum and various
bronchoscopically obtained specimens for MTB among 30 patients with positive
26

MTB cultures from any bronchoscopic specimens. They found that bronchoscopy did
not statistically improve immediate or ultimate MTB diagnosis over sputum alone.
Transbronchial lung biopsy did not make additional contributions to the diagnosis of
pulmonary TB. (24) Levy et al. commented that bronchial washings should not be the
sole procedure utilized when bronchoscopy was performed. Transbronchial lung
biopsy remained a valuable procedure to confirm pulmonary TB in patients whose
sputum was culture-negative for mycobacteria.(22) In this study, transbronchial lung
biopsy was performed selectively in 19 patients at the discretion of the endoscopists.
The sensitivity of its histology was 26.3%, although lower than that of sputum AFB
culture (45.5%), but it provided an alternative method other than sputum AFB smear
for early diagnosis, as the histological results were often available within two to three
days in our centre, much earlier than the AFB culture results. In addition, it was the
exclusive diagnostic test in two patients. The transbronchial lung biopsy specimens
were all AFB smear negative in this study, but the sensitivity of their AFB culture was
slightly higher than that of sputum (50% vs 45.5%). Although this study failed to
demonstrate any significant role for transbronchial lung biopsy in early diagnosis of
SNN-TB, it did provide the only positive result for pulmonary TB in one patient, and
treatment could then be confidently started. The relatively low yield on transbronchial
biopsy culture was probably related to the small area being sampled by the biopsy
27

needle as compared to other bronchoscopic sampling technique like bronchial

lavage.(10, 22) Stenson et al. suggested that fragmenting the biopsy tissue prior to
culture might help to increase the culture yield.(10) As transbronchial biopsy can
result in complications including pneumothorax and uncontrolled bleeding, some
authors recommend that it should be reserved for patients in whom initial
bronchoscopy is non-diagnostic.(23) Further prospective study with a bigger sample
size was necessary to confirm the role of transbronchial lung biopsy culture in
diagnosing SSN-TB.
The relatively low sensitivity of AFB culture from bronchoscopic sampling
techniques could be due to the use of lignocaine. The effect of local anaesthetic used
on the microbiological yield of bronchoscopic secretions has been well documented.
(1, 8, 13, 23) Wallace et al. found that the yield of the bronchoscopic specimens on
culture was lower than that obtained from prebronchoscopy sputum (44% and 67%
respectively), although the low sensitivity from bronchoscopy may be attributed to the
inhibition of mycobacterial growth by local anaesthetic agent used during the
procedure.(1, 13) Stenson et al suggested that reducing the amount of lidocaine used
during bronchoscopy and hence their antibacterial effects might increase the culture
yield.(10) It has been shown that when two milliliters of xylocaine was used, the
bronchial aspirate could contain up to 1% lignocaine and that most strains of MTB are
28

inhibited by a concentration of 0.5%.(1) Jalleh RD et al. suggested that during the

process of aspiration, the first two aliquots (10-20ml each) of saline instilled into the
respective segmental orifice be utilized for direct smear and cytological examination
only, while the subsequent two aliquots should then be collected separately and sent
for culture. They believed that in this way, the inhibitory effect of lignocaine on the
growth of MTB could be overcome.(11) Although in this study, the specific site of
applying lignocaine was not mentioned in the clinical records, its direct effect on
culture results could not be confidently assessed. But the fact that the amount of local
anaesthetic used can influence the microbiological results obtained from
bronchoscopic secretions need to be kept in mind while evaluating SSN-TB patients
with bronchoscopic methods in order to optimize the diagnostic yield.(1) It should be
used in the lowest possible quantities compatible with adequate analgesia.(8)
The role of other diagnostic tests for pulmonary TB should not be understated.
The sensitivity of AFB culture from early morning gastric aspirate was 25% in this
study. Other tests including CT guided transthoracic fine needle aspiration cytology
(FNAC), CT imaging, chest tapping and thoracoscopic lung biopsy provided
diagnosis for nearly 30% of SNN-TB in this study. High resolution CT (HRCT) has
been found reliable in diagnosing miliary tuberculosis.(25) Non-conventional
bronchoscopic diagnostic methods including serodiagnostic methods, tuberculostearic
29

acid estimation, adenosine deaminase and lysozyme estimation, and lactate

dehydrogenase estimation has been evaluated by various studies in the past, but their
diagnostic value were not consistently reliable, not to mention that they were seldom
used in clinical practice.(1) Molecular methods like polymerase chain reaction could
be a useful adjunct to other conventional bronchoscopic sampling techniques in
diagnosing SSN-TB in the appropriate clinical setting.(1, 26) Unfortunately,
molecular study only operates once a week in our center, which may have delayed the
availability of the results, and limited its role in providing immediate diagnosis and
being the exclusive tests for SSN-TB subjects.
Various conventional bronchoscopic sampling techniques appeared helpful in the
diagnosis of pulmonary TB, especially in sputum smear negative cases. However,
flexible bronchoscopy is a costly test, is an invasive procedure, and is not widely
available in the developing countries and resource scarce settings. Judicious use of the
procedure is always necessary. In developed countries with no limitations on
resources or diagnostic facilities, early use of flexible bronchoscopy seems to be the
best course of action in patients having suspected SSN-TB.(1) Combining various
bronchoscopic sampling techniques help increasing the diagnostic yield, and hence
improving the ability to document active tuberculosis, thus minimizing unnecessary
thoracotomy and expedite the administration of appropriate medications.(11, 12, 16,
30

22) Other diagnostic techniques including sputum induction and gastric aspirate etc
have to be considered as well. Empirical anti-tuberculous treatment might be
appropriate in selected cases.(1, 12, 23) In HIV-infected patients with pulmonary
disease, the absence of acid-fast organisms on a smear of bronchoscopic specimens or
the absence of granulomata on transbronchial biopsy does not exclude tuberculosis.
When bronchoscopy was not diagnostic, but unexplained CXR findings suggested
tuberculosis, empirical anti-tuberculous therapy should be administered until results
of mycobacterial culture were available. This strategy helped to limit morbidity,
mortality, and transmission of tuberculosis in patients with HIV infection.(23) Levy et
al. reviewed a series of 35 patients with pulmonary tuberculosis diagnosed by flexible
fibreoptic bronchoscopy and transbronchial lung biopsy after three sputum specimens
had been smear-negative for acid fast bacilli. They found that if bronchoscopy had
been delayed until the results of mycobacterial culture of the sputum were made
available and no further investigations had been performed, 34.3% of patients would
not have required the procedure. They therefore recommended that if the patients
clinical status permitted, bronchoscopy should be delayed until preliminary
mycobacterial culture results were available. However, careful follow-up of patients
was mandatory because lesions could progress rapidly.(22) In all circumstances,
diagnostic algorithms should be tailored to the needs of the individual countries and
31

adapted for local use as appropriate.(1, 11)

32

Conclusions
Tuberculosis remains the leading cause of mortality from any infectious human
pathogen, resulting in an estimated three million deaths annually worldwide.(23)
While sputum examination remains the most important method for confirming the
diagnosis of pulmonary TB, flexible fibreoptic bronchoscopy with transbronchial lung
biopsy has been accepted as a safe and useful procedure for evaluating patients who
were clinically suspected of having tuberculosis but produced sputum that was
smear-negative for acid-fast bacilli.(8, 10, 11, 17, 22) Standard bronchsocopic
procedures, including bronchial washings, bronchial brushing, and transbronchial
biopsy, showed a diagnostic efficacy ranging from 43 to 78%.(16, 27) The procedure
is technically straightforwards, although the best yields and fewest complications are
obtained by a skilled bronchoscopist with moderate experience with the procedure.(17)
In particular, bronchoalveolar lavage has been used with great success as a tool for
recovering pathogenic micro-organisms from the lower respiratory tract of individuals
with pulmonary infiltrates.(17) In areas with high prevalence of pulmonary TB,
routine performance of bronchoalveolar lavage for AFB smear and culture is useful in
the early diagnosis and treatment. Different pulmonary specimens and bronchoscopic
sampling techniques should also be used as an adjunct to clinical and radiographic
evidence of disease to optimize the diagnostic yield.(1, 22)

33

References
1.

Mohan A, Sharma SK. Fibreoptic bronchoscopy in the diagnosis of sputum

smear-negative pulmonary tuberculosis: current status. Indian Journal of Chest

Diseases and Allied Sciences. [Review]. 2008 Jan-Mar;50(1):67-78.
2.

Parimon T, Spitters CE, Muangman N, Euahrongchit J, Oren E, Narita M.

Unexpected pulmonary involvement in extrapulmonary tuberculosis patients. CHEST.

2008;134:589.
3.

Tam CM, Kam KM, Leung CC, Law WS, Mok YW, Yew WW, et al. Guidelines

on the management of multidrug-resistant and extensively drug-resistant tuberculosis

in Hong Kong. Annual Report (Suppl) 2008. 2008 December
4.

Tuberculosis and Chest Service, Department of Health. Tuberculosis Manual.

2006.
5.

TB & Chest Service, Department of Health. Annual Report. 2009.

6.

Maartens G. Advances in adult pulmonary tuberculosis. Current Opinions in

Pulmonary Medicine. 2002;8:173 - 7.

7.

Bell D, Leckie V, McKendrick M. The role of induced sputum in the diagnosis of

pulmonary tuberculosis. Journal of infection 2003;47:317 - 21.

8.

Willcox PA, Benatar SR, Potgieter PD. Use of the flexible fibreoptic

bronchoscope in diagnosis of sputum-negative pulmoanry tuberculosis. Thorax. 1982

Aug;37(8):598-601.
34

9.

Chang KC, Leung CC, Yew WW, Tam CM. Supervised and induced sputum

among patients with smear-negative pulmonary tuberculosis. European Respiratory

Journal. 2008;31:1085-90.
10. Stenson W, Aranda C, Bevelaqua FA. Transbronchial biopsy culture in
pulmonary tuberculosis. Chest. 1983 Jun;83(6):883-34.
11. Jalleh RD, Kuppusamy I, Parameswary V, Yeow CS. Fibreoptic bronchoscopy in
the diagnosis of pulmonary tuberculosis: a Malaysian experience. Singapore Medical
Journal. 1993;34:55-7.
12. Chan

HS,

Sun

HMA,

Hoheisel

GB.

Bronchoscopic

aspiration

and

bronchoalveolar lavage in the diagnosis of sputum smear negative pulmonary

tuberculosis. Lung. 1990;168:215-20.
13. Wallace JM, Deutsch AL, Harrell JH, Moser KM. Bronchsocopy and
transbronchial biopsy in evaluation of patients with suspected active tuberculosis.
American Journal of Medicine. 1981;70:1189-94.
14. Jett JR, Cortese DA, Dines DE. The value of bronchoscopy in the diagnosis of
mycobacterial disease. Chest. 1981;80:575-8.
15. Funahashi A, Lohaus GH, Politis J, Hranicka LJ. Role of fiberoptic
bronchoscopy in the diagnosis of mycobacterial diseases. Thorax. 1983;38:267-70.
16. Lai RS, Lee SS, Ting YM, Wang HC, Lin CC, Lu JY. Diagnostic value of
35

transbronchial lung biopsy under fluoroscopic guidance in solitary pulmonary nodule

in an endemic area of tuberculosis. Respiratory Medicine. 1996 Mar;90(3):139-43.
17. Charoenratanakul S, Dejsomritrutai , Chaiprasert A. Diagnostic role of fiberoptic
bronchoscopy in suspected smear negative pulmonary tuberculosis. Respiratory
Medicine. 1995 Oct;89(9):621-3.
18. Pue CA, Pacht ER. Complications of fiberoptic bronchoscopy at a university
hospital. Chest. 1995;107(2):430-2.
19. Kvale PA, Johnson MC, Wroblewski DA. Diagnosis of tuberculosis: routine
cultures of bronchial washings are not indicated. Chest. 1979;76:140-2.
20. So SY, Lam WK, Yu DYC. Rapid diagnosis of suspected pulmonary tuberculosis
by fiberoptic bronchoscopy. Tubercle. 1982;63:195-200.
21. Ip M, Chau PY, So SY, Lam WK. The value of routine bronchial aspirate culture
at fiberoptic bronchoscopy for the diagnosis of tuberculosis. Tubercle. 1989;70:281-5.
22. Levy H, Feldman C, Kallenbach JM. The diagnostic yield of prebronchoscopy
sputa and bronchial washings in patients with biopsy-proven pulmonary tuberculosis.
South Africa Medical Journal 1989 Jun 3;75(11):527-8.
23. Kennedy DJ, Lewis WP, Barnes PF. Yield of bronchoscopy for the diagnosis of
tuberculosis in patients with human immunodeficiency virus infection. Chest. 1992
Oct;102(4):1040-4.
36

24. Miro AM, Gibilarra E, Powell S, Kamholz SL. The role of fiberoptic
bronchoscopy for the diagnosis of pulmonary tuberculosis in patients at risk for AIDS.
Chest. 1992;101:1211-4.
25. Pipavath SN, Sharma SK, Sinha S, Mukhopadhyay S, Gulati MS. High
resolution CT (HRCT) in miliary tuberculosis (MTB) of the lung: correlation with
pulmonary function tests and gas exchange parameters in north Indian patients. Indian
Journal of Medical Research. 2007 Sep;126(3):193-8.
26. Wong CF, Yew WW, Wong PC, Lee J. A case of concomitant tuberculosis and
sarcoidosis with mycobacterial DNA present in the sarcoid lesion. Chest 1998
Aug;114(2):626-9.
27. Reichenberger F, Weber J, Tamm M, Bolliger CT, Dalquen P, Perruchoud AP, et
al. The value of transbronchial needle aspiration in the diagnosis of peripheral
pulmonary lesions. Chest. 1999 Sep;116(3):704-8.

37

Tables and figures

Table 1. Diagnostic methods used for the microbiological/histopathological
diagnosis in patients suspected of having pulmonary tuberculosis but were sputum
smear-negative or produced inadequate sputum1
Diagnostic methods
Sputum induction with hypertonic saline
Transtracheal needle aspiration
Radiologically guided transthoracic needle aspiration
Gastric lavage
Bronchoscopic procedures
Rigid bronchoscopy
Flexible fibreoptic bronchoscopy
Bronchial aspirate
Bronchial washings
Bronchial brush smear
Bronchoalveolar lavage
Bronchial biopsy
Transbronchial lung biopsy
Post-bronchoscopy sputum
Others
Peripheral blood examination using serological and molecular methods
1

Adapted from Mohan A, Sharma SK. Fibreoptic bronchoscopy in the diagnosis of sputum

smear-negative pulmonary tuberculosis: current status. Indian J Chest Dis Allied Sci 2008
Jan-Mar;50(1):67-78.
38

18

New case
16

Relapse case

14

Treatment after default

12
10
8
6
4
2
0

Case category

Figure 1.

Case category for subjects having pulmonary tuberculosis. (N=22) New

case: patients having active pulmonary TB, who have never been diagnosed of having
the disease and have never received anti-tuberculous drugs before. Relapse case:
patients diagnosed of having active pulmonary TB who have completed
anti-tuberculous drugs before. Treatment after default: patient diagnosed of having
active pulmonary TB, who have previously interrupted anti-tuberculous treatment for
two consecutive months or more.

Table 2.

Baseline characteristics of subjects having pulmonary tuberculosis (N=22)

Characteristics

Number (%)

Sex
Male

17(77.3%)

Female

5(22.7%)

Age
18-30

2(9.1%)

31-40

0
39

(Table 2 continuation)
Characteristics

Number (%)

41-50

4(18.2%)

51-60

3(13.6%)

61-70

3(13.6%)

>70

10(45.5%)

Living status
OAH1

1(4.5%)

Lives with family

19(86.4%)

Lives alone

2(9.1%)

Pre-morbid ADL2 status

Independent

20(90.9%)

Partially dependent

2(9.1%)

Dependent

Smoking status
Smoker

8(36.4%)

Ex-smoker3

3(13.6%)

Non-smoker

7(31.8%)

Unknown

4(18.2%)

Contact history reported

Yes

1(4.5%)

No

21(95.5%)

OAH Old age home

ADL Activity of daily living

Ex-smoker referred to subjects who have quitted smoking for more than one year

40

Diabetes Mellitus
Alcoholism
Other malignancy
Chronic renal failure
On steroid
Lung cancer
HIV
General debilitation
Nil

8
Risk factors

Figure 2.

Risk factors for pulmonary tuberculosis among patients having

mycobacterial diseases. Three subjects got more than one risk factor. (N=22)

Table 3.

Application of sedatives for pre-med (N=22)

Number of subjects received1(%)

Sedatives
Pethidine

21 (95.5%)

2% Xylocaine jelly

19 (86.4%)

Xylocaine spray

16 (72.7%)

Midazolam

2 (9.1%)

Some patients received more than one sedative.

41

Suspected TB

BSS

Solitary pulmonary
nodule

Unresolved pneumonia

Suspected lung cancer

10

Indications for bronchoscopy

Figure 3. Indications for bronchoscopy among patients having pulmonary

tuberculosis. (N=22) One subject was indicated for bronchoscopy because of having
BSS and suspected having tuberculosis. (TB tuberculosis; BSS blood stained sputum)

42

2(9.1%)

No abnormality detected
Mucosal lesions

20(90.9%)

Figure 4. Bronchoscopy findings among subjects having pulmonary tuberculosis.

(N=22)

Table 4.

Radiological features of subjects having pulmonary tuberculosis. (N=22)

Extent of disease
Minimal (total area <

Number (%)

Radiological feature

Number (%)

13(59.1%)

Infiltrates

8(36.4%)

Moderate (>RUL1)

7(31.8%)

Nodule

7(31.8%)

Advanced (>1 lung)

2(9.1%)

Cavitatory

5(22.7%)

Military

1(4.5%)

Effusion

1(4.5%)

RUL1)

Right upper lobe

43

Table 5.

Diagnostic yield of individual tests in pulmonary tuberculosis

Individual test

Number of applications (%)

Sensitivity* (%)

Bronchoalveolar lavage
1

22(100%)

3/22(13.6%)

22(100%)

6/22(27.3%)

14(63.6%)

5/14(35.7%)

1(4.5%)

0/1(0%)

19(86.4%)

5/19(26.3%)

6(27.3%)

0/6(0%)

6(27.3%)

3/6(50%)

22(100%)

0/22(0%)

22(100%)

10/22(45.5%)

4(18.2%)

0/4(0%)

4(18.2%)

1/4(25%)

AFB smear
AFB culture
MTB direct test
Bronchial brush cytology
Transbronchial lung biopsy
Histology
AFB smear
AFB culture
Sputum
AFB smear
AFB culture
Early morning gastric aspirate
AFB smear
AFB culture
Other diagnostic tests3

7/22(31.8%)

CT3 guided transthoracic FNAC4

2(9.1%)

CT3 thorax

2(9.1%)

Pleural fluid AFB1 culture

1(4.5%)

Thoracoscopic lung biopsy

1(4.5%)

Repeating bronchoscopy

1(4.5%)
44

(Table 5 continuation)
*

Sensitivity was calculated by number of patients in whom test was positive/number of patients in whom

test was performed

1

Acid-fast Bacilli

2Mycobacterial tuberculosis
3

Computed tomography

Fine needle aspiration cytology

3(13.6%)

BAL AFB smear

1(4.5%)

7(31.8%)

BAL AFB culture

2(9.1%)

BAL MTB direct

test
TBLB histology
TBLB AFB culture

2(9.1%)
1(4.5%)

Others

1(4.5%)

5(22.7%)

Figure 5.

Gastric aspirate AFB

culture
Sputum AFB culture

Frequency of individual tests as the exclusive means for diagnosing

pulmonary tuberculosis. (N=22; BAL bronchoalveolar lavage; AFB acid fast bacilli;
MTB Mycobacterium tuberculosis; TBLB transbronchial lung biopsy)

Table 6.

Complications of bronchoscopy among subjects having pulmonary

tuberculosis. (N=22)
Complications

Number(%)

Nil

21(95.5%)

Hemorrhage

1(4.5%)

45