i n d i a n j o u r n a l o f t u b e r c u l o s i s 6 6 ( 2 0 1 9 ) 1 3 4 e1 3 8

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Original article

Changes of CRP serum levels in pulmonary TB

patients with AFB smear-positive sputum before
and two months after receiving anti-tuberculosis
drug treatment

Soedarsono Soedarsono*, Mochamad Cahyo Subiantoro

Department of Pulmunology and Respiratory Medicine, Faculty of Medicine, Airlangga University, Dr. Soetomo
General Hospital, Surabaya, Indonesia

article info abstract

Article history: Background: Pulmonary tuberculosis (TB) produces an inflammatory process of the lung
Received 26 February 2018 parenchyma. While effective treatment of pulmonary TB and disease resolution processes
Accepted 26 July 2018 have an impact on decreasing inflammatory conditions of the pulmonary parenchyma.
Available online 12 October 2018 This stimulates researchers to investigate changes in lung parenchymal inflammatory
conditions detected from changes of C-reactive protein (CRP) serum levels pre and post two
Keywords: months of anti-tuberculosis drug treatment.
Pulmonary Tuberculosis Objectives: To know the changes of CRP serum levels in pulmonary TB patients with Acid
The Positivity of Acid Fast Bacilli Fast Bacillus (AFB) smear-positive sputum before and 2 months after receiving anti-
Sputum Conversion tuberculosis drug treatment.
CRP Serum Method: This study used prospective cohort study design, conducted in pulmonary outpatient
unit at Dr. Soetomo General Hospital Surabaya from March to June 2013. Sample size was 30
pulmonary TB patients with AFB smear-positive sputum. AFB sputum grading and CRP serum
level was measured before and 2 months after receiving anti-tuberculosis drug treatment.
International Union Against Tuberculosis and Lung Disease (IUATLD) scale was used for AFB
sputum grading. CRP serum was measured using immunoturbidimetric method.
Result: The average CRP serum levels of pre anti-tuberculosis drug treatment were 6.48 ± 4.27
mg/dL in males and 6.28 ± 5.26 mg/dL in females. After two months of anti-tuberculosis drug
treatment, the average CRP serum levels were 1.21 ± 1.94 mg/dL in males and 1.21 ± 1.22 mg/
dL in females. Sputum conversion occurred in 27 out of 30 samples after two months of anti-
tuberculosis drug treatment.
Conclusion: The CRP serum levels was not significantly different in patients with pulmonary
TB who experienced sputum conversion compared to patients without sputum conversion
after two months of anti-tuberculosis drug treatment.
© 2018 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.

* Corresponding author.
E-mail address: ssoedarsono@gmail.com (S. Soedarsono).
https://doi.org/10.1016/j.ijtb.2018.07.007
0019-5707/© 2018 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.
 i n d i a n j o u r n a l o f t u b e r c u l o s i s 6 6 ( 2 0 1 9 ) 1 3 4 e1 3 8
1. Background
Although Tuberculosis (TB) is a curable disease, it is still the
most infectious disease with high mortality rate in the world.
Despite the progress and expansion of Directly Observed
Treatment Short course (DOTS) program and the increased
success rate of therapy, inadequate case detection is still a
major problem for TB infection control. In the last decade, ef-
forts for diagnosing and evaluating the therapy in most TB
infection cases are still not optimal, thus inhibiting the exter-
mination of this disease. Nowadays the focus is on the research
and development for diagnostic, therapeutic, and vaccine fa-
cilities especially in area with low healing rates. Medical
treatments, vaccines, immunity status, and concomitant dis-
eases disrupt the balance between host and pathogens, in
which affecting the clinical outcomes and the prognosis.1,2
Detection of TB cases is still quite difficult, because diag-
nostic methods available are less sensitive or inaccurate. Even
with new diagnostic methods, it is still difficult to detect
several cases such as Acid Fast Bacillus (AFB) smear-negative
sputum, TB in children, and reactivation of latent TB infec-
tion. Although new and more sensitive diagnostic methods are
already available to detect TB and drug resistance, but simple
and inexpensive diagnostic methods have not been found yet.1
There are some efforts to use biomarker as a simple and
inexpensive diagnostic methods for TB infection. These
currently available biomarkers are AFB sputum smear and
Mycobacterium Tuberculosis (Mtb) sputum culture. However,
both biomarkers still have limitations. For Mtb sputum culture,
the required time to obtain the results are very long, causing
diagnostic and treatment evaluation become less efficient.
While in AFB sputum smear examination, it has limitation in
Human Immunodeficiency Virus (HIV)-infected patients and
among patients with severe immune disorders because this
kind of patients usually have an AFB smear-negative sputum
result. It also has limitation in patients who have received TB
treatment, because patients often have no cough or reduced
cough frequency with minimal sputum production. This can
lead to false-negative results on sputum re-examination.1,3
C-reactive protein (CRP) is one of the biomarkers in the
blood that exhibits macrophage activation in lung tubercu-
losis, other biomarkers that exhibit macrophage activation are
Neopterin, soluble Intercellular Adhesion Molecule-1 (sICAM-
1) and Procalcitonin. CRP levels increases compared to baseline
values in the event of disease progression and will decrease
with successful treatment.1,4 In several studies of CRP exami-
nation in pulmonary tuberculosis patients, CRP serum levels
were increased in TB-infected patients, especially in pulmo-
nary TB patients with AFB smear-positive sputum and their
levels were greatly increased in pulmonary TB patients with
more severe lung tissue damage.5,6 Other studies had shown
that anti-tuberculosis drug treatment and sputum conversion
resulting progressive decrease in CRP levels to normal levels
that indicating an effective therapeutic response.7e9 Thus, CRP
examination is expected to evaluate TB therapy and curing
treatment in a simple and inexpensive way. However, in
Indonesia this kind of study is still limited, moreover the dif-
ference in nutritional status and polymorphism of Indonesian
gene with other people in the world that may affect the
135
immunity status of Indonesians against tuberculosis and it can
provide different results of the research.
2. Method
This study was observational prospective cohort analysis
study, conducted in pulmonary outpatient unit at Dr. Soetomo
General Hospital Surabaya from March to June 2013. Subjects of
the study were pulmonary TB patients with AFB smear-positive
sputum. Total samples for this study was 30 patients. Inclusion
criteria for this study was patients aged 15e70 years old
and never received anti-tuberculosis drug treatment before.
Exclusion criteria for this study was patients with one or more
of the following comorbid: Multi-drug resistant (MDR) TB, HIV,
Type 2 Diabetes mellitus (T2DM), cancer, heart disease, Sys-
temic Lupus Erythematosus (SLE), rheumatoid arthritis, acute
pancreatitis, and acute infections.
CRP serum level and AFB sputum grading were measured
twice, before treatment and 2 months after receiving anti-
tuberculosis drug treatment. Anti-tuberculosis drug treat-
ment given was according to WHO guideline. CRP serum level
was measured using immunoturbidimetric method. By this
method, the lowest detectable CRP serum level was 0.3e0.5
mg/dL. CRP serum level result was divided into 5 levels;
normal (<0.5 mg/dL), trace (0.5e0.9mg/dL), slightly increase
(1e4.9 mg/dL), moderate increase (5e100 mg/dL), and highly
increase (>100 mg/dL). For AFB smear sputum grading, Inter-
national Union Against Tuberculosis and Lung Disease
(IUATLD) scale was used. SPSS (SPSS, Inc., Chicago, IL) data
analysis was used in this study. A p value <0.05 was consid-
ered significant.
3. Result
3.1. Respondents' characteristics
The subjects of this study were 30 patients with smear posi-
tive pulmonary tuberculosis. Most of them were men (17
people, 56.7%). The most age range was 20e35 years (3 people,
43.3%, Table 1).
3.2. CRP serum examination before anti-tuberculosis
drug treatment
Different value of CRP serum levels based on sex was p ¼ 0.908
(p > 0.05). Different value of CRP serum levels based on age
range was p ¼ 0.920 (p > 0.05; Table 2). The most CRP levels
was on the range of 5e8 mg/dL (17 people, 57%) and most of
the subjects was AFB 1þ (16 people, 53%). The dominant dis-
tribution before anti-tuberculosis drug treatment was sub-
jects with AFB 1 þ and having CRP levels of 5e100 mg/dL (9
people, 30%, Table 3).
3.3. CRP serum examination 2 months after anti-
tuberculosis drug treatment
Different values of CRP serum levels based on sex obtained
p ¼ 0.995 (p > 0.05). Different values of CRP serum levels based
136 i n d i a n j o u r n a l o f t u b e r c u l o s i s 6 6 ( 2 0 1 9 ) 1 3 4 e1 3 8

Table 1 e Subjects characteristic. 4. Discussion

Characteristic Frequency Percentage
Sex
Most studies reported that there was no association between
Male 17 56.7 age (20e70 years) and CRP serum levels.5,10e12 Although, there
Female 13 43.3 were studies reporting minimal increase of CRP serum levels
Age as age increased. In the study, researchers did not exclude the
20e35 Years 13 43.3 possibility of age-related obesity incidence, or subclinical and
36e50 Years 11 36.7
seasonal inflammatory problems.13 While gender factor re-
51e65 Years 4 13.3
ported not having effect of CRP serum levels.5
>65 Years 2 6.7
In pulmonary TB patients who had not received TB treat-
ment, there would be an inflammatory process of lung tissue,
an increased activity of pulmonary macrophages that would
Table 2 e The CRP serum level examination based on sex increase CRP serum levels. In patients with active pulmonary
and age before anti-tuberculosis drug treatment.
TB without lung tissue damage, there would be a moderate
Characteristic Average of CRP ± SD (mg/dL) p increase of CRP serum levels, and their levels might be
Sex increased in patients with active pulmonary TB, accompanied
Male 6.48 ± 4.27 by extensive lung tissue damage.5
Female 6.28 ± 5.26 0.908 The results were in accordance with other studies world-
Age wide that mentioned in patients with active pulmonary TB
20e35 Years 6.76 ± 4.15
who had not received treatment would experience moderate
36e50 Years 6.63 ± 5.67 0.920
51e65 Years 5.20 ± 4.77
levels increased of CRP serum levels as other studies that ob-
>65 Years 5.10 ± 4.27 tained average CRP of 5.57 mg/dL in pulmonary TB with normal
thrombosis and 9.54 mg/dL in pulmonary TB with thrombo-
cytosis.11 Another study obtained an average CRP level of 9.86
mg/dL in pulmonary TB patients prior to anti-tuberculosis
on age range obtained p ¼ 0.071 (p > 0.05; Table 4). Most CRP treatment.5 Some studies mentioned that AFB grading score
serum levels was in the range of 0.5e0.9 mg/dL (16 people, had a correlation through CRP serum levels. This meant that
53%) and the most subjects were AFB smear-negative (27 patients with AFB sputum level 3 þ had higher CRP levels than
people, 90%). The dominant distribution after 2 months of patients with AFB sputum level 2þ, 1þ, and 0.14
anti-tuberculosis drug treatment was AFB smear-negative and The results of this study were not in accordance with the
having CRP levels in the range of 0.5e0.9 mg/dL (16 people, results of previous research which stated that AFB grading
53%, Table 5). score had a positive correlation with CRP serum levels.14 But
this was consistent with other studies suggesting that CRP did
3.4. Changes in pre and post 2-months anti-tuberculosis not increase significantly with higher bacterial load, but CRP
drug treatment values increased significantly with a more severe degree of
disease according to chest radiograph.15 This fact was caused
Before given anti-tuberculosis drug treatment for 2 months, 30 by the Mycobacterium tuberculosis bacteria in the lung of pul-
patients had AFB positive-smear sputum. After received anti- monary tuberculosis patients related to the inflammatory
tuberculosis drug treatment, sputum conversion occurred in process of lung tissue that correlated with CRP levels changes.
27 out of 30 patients. 2 months after receiving anti-tuberculosis However, the pulmonary inflammatory process was not only
drug treatment, subjects with moderate increased CRP serum influenced by the large population of TB germs, but the pres-
levels were 17 people (57%) and after receiving treatment were ence of lung damage processes more influenced the inflam-
11 people (37%, Table 6). There were significant differences in mation rate of lung tissue that affected the higher CRP serum
CRP serum level before and 2 months after receiving 2 months level. Here we did not evaluate the extent of lung damage
anti-tuberculosis drug treatment (5.45 vs 0.55 mg/dL; based on chest radiographs which allowed the CRP results to
p ¼ 0.0001). There is no correlation between CRP level changes have no correlation with AFB grading score in pulmonary TB
and sputum conversion (p ¼ 0.509). patients prior to anti-tuberculosis drug treatment.

Table 3 e AFB smear-positive sputum grading based on CRP level before anti-tuberculosis drug treatment.
AFB Grading CRP Serum Level (mg/dL)
<0.5 0.5e0.9 1e4.9 5e100 >100 Total
e e e e e e 0 (0%)
Scanty e e 1 (3%) 1 (3%) e 2 (7%)
1þ e 2 (7%) 5 (17%) 9 (30%) e 16 (53%)
2þ e 1 (3%) 2 (7%) 5 (17%) e 8 (27%)
3þ e 1 (3%) 1 (3%) 2 (7%) e 4 (13%)
Total e 4 (13%) 9 (30%) 17 (57%) e 30 (100%)
 i n d i a n j o u r n a l o f t u b e r c u l o s i s 6 6 ( 2 0 1 9 ) 1 3 4 e1 3 8 137

immunoturbidimetric method. Future study with larger

Table 4 e The CRP serum level of TB patients based on sex
samples should be done to confirm that there is no correlation
and age 2 months after anti-tuberculosis drug treatment.
between CRP serum level in pulmonary TB patients with and
Characteristic Mean CRP ± SD (mg/dL) p value
without sputum conversion.
Sex
Male 1.211 ± 1.937 0.995
Female 1.215 ± 1.225 6. Conclusion
Age
20e35 Years 0.853 ± 0.954 There was no significant difference in CRP levels of pulmonary
36e50 Years 1.036 ± 0.966 0.071
TB patients with sputum conversion compared to those
51e65 Years 3.175 ± 3.625
without sputum conversion after 2 months of anti-
>65 Years 0.600 ± 0.424
tuberculosis drug treatment.

Table 5 e Samples distribution based on AFB sputum and CRP level 2 months after anti-tuberculosis drug treatment.
AFB grading CRP Level (mg/dL)
<0.5 0.5e0.9 1e4.9 5e100 >100 Total
e 10 (33%) 16 (53%) e 1 (3%) e 27 (90%)
Scanty e e e e e e
1þ e e 2 (7%) e e 2 (7%)
2þ 1 (3%) e e e e 1 (3%)
3þ e e e e e e
Total 11 (36%) 16 (53%) 2 (7%) 1 (3%) e 30 (100%)

Table 6 e The CRP level changes before and 2 months after anti-tuberculosis drug treatment.
After anti-tuberculosis drug Treatment
CRP level Normal Trace Mild increase Moderate increase Total
Before anti-tuberculosis treatment Normal 0 0 0 0 0
Trace 2 1 1 0 4
Mild increase 3 4 2 0 9
Moderate increase 6 3 7 1 17
Total 11 8 10 1 30

The success of TB treatment after 2 months was shown

from clinical conditions recovery or decreased symptoms of
the patient with decreased TB germ populations up to unde-
Conflicts of interest
tectable conditions that was shown in sputum conversion in
AFB sputum evaluation results after anti-tuberculosis drug
The authors have none to declare.
treatment and this correlated with decreased inflammatory
conditions of lung tissue. The presence of pulmonary
inflammation resolution was indicated by a decrease of CRP
levels to normal level.7,8 Acknowledgements
This indicates an inflammatory condition decrease of lung
tissue following the administration of anti-tuberculosis drug Thank you to clinical microbiology laboratory and clinical
treatment in pulmonary tuberculosis patients characterized pathology laboratory, DR. Soetomo General Hospital.
by a decrease of CRP levels. The results of this study were also
in line with previous studies which stated that the anti-
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