CORRELATION OF ASYMPTOMATIC AND SYMPTOMATIC HYPERURICEMIA WITH

SPUTUM CONVERTION TIME AND OUTCOME IN DRUG RESISTANCE

TUBERCULOSIS PATIENTS IN DR MOEWARDI HOSPITAL SURAKARTA

Yanuar, Jatu Aphridasari

Department of Pulmonology and Respiratory Medicine
Medical Faculty of Sebelas Maret University / Dr. Moewardi General Hospital
Surakarta

Abstract

Background: Drug-resistant tuberculosis (DR TB) patients often experience either

asymptomatic or symptomatic hyperuricemia as a side effect of DR TB treatment. Studies
on the association between clinical manifestations of hyperuricemia and the outcome of
DR-TB patients are limited. Therefore, this study was conducted to investigate the
corellation between clinical manifestations of hyperuricemia and sputum conversion time
as well as the outcome of DR TB patients.

Methods: An analytic observational study using a retrospective cohort design was

conducted on DR TB patients undergoing treatment in Dr. Moewardi Hospital, Surakarta,
from January 2018 to December 2022. The data were taken from the medical records of
patients and statisfically analysed with Spearman Correlation test. The significance level
was determined with p< 0.05

Results: Hyperuricemia occurred in 90 of 313 subjects (28,7%), comprising 58 subjects

(64.4%) with asymptomatic hyperuricemia and 32 (35.6%) subjects with symptomatic
hyperuricemia. The Spearman correlation test obtained no correlation between clinical
manifestations of hyperuricemia and sputum conversion time (p = 784) as well as
outcome (p = 0.821). Our analysis found no difference in terms of outcome and sputum
conversion time among DR TB patients either with asymptomatic or symptomatic
hyperuricemia who were on short term regimens (STR) using kanamycin/amikacin as well
as all oral regimens and long term regimens ( p = 0.357 and p = 0.141; p = 0.619 and p =
0.478; p = 0.255 and p = 0.938, respectively).

Conclusion: Clinical manifestations of hyperuricemia do not affect the conversion time or

outcome of DR TB patients undergoing treatment.

Keywords: hyperuricemia, drug resistance tuberculosis, outcome, sputum conversion

time

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INTRODUCTION
Tuberculosis is one of the top ten leading causes of death around the globe, in
which the primary cause of death is infection.1 The 2021 Global TB Report states that
78% of drug-resistant TB (DR-TB) cases are rifampicin-resistant TB (RR) cases with a
total of 465,000 cases.2 Indonesia ranks fifth in DR-TB with an estimated case of 2.4% of
all new TB patients and 13% of TB patients receiving therapy.3
High mortality and low success of DR-TB treatment remain a health problem in
Indonesia. The therapy for DR-TB is expensive, less effective, and associated with more
side effects than drug-susceptible TB. In addition they take long period as a result, the
success rate of TB DR treatment remains less than 60% globally, and a large number of
patients die each year.4,5 Sputum culture conversion has been proven to be of assistance
for predicting the efficacy of TB treatment, while sputum bacteriological conversion has
been reported as a useful indicator of DR-TB therapy outcomes.6 We conducted this
study to describe and analyze the relationship between therapeutic regimens,
symptomatic and asymptomatic hyperuricemia on sputum conversion and treatment
outcomes in drug-resistant TB patients at dr Moewardi Hospital, Surakarta.

METHODS
We carried out an analytic observational study using a retrospective cohort design
on DR-TB patients treated in Dr. Moewardi Hospital, Surakarta, Indonesia between
January 2018 and December 2022. We included patients diagnosed with DR-TB aged
over 18 years old who were treated in Dr Moewardi Hospital . Patients who did not have
hyperuricemia in the first month after initiating the therapy and complete data were
excluded from the study. The secondary data were taken from medical records. The
independent variables were hyperuricemia classified into symptomatic and asymptomatic,
and drug resistance therapy regimens classified into kanamycin/amikacin-containing
Short Term Regimens (STR), all oral STR, and Long Term Regimens (LTR), while the
dependent variables were clinical outcomes and sputum conversion time. Hyperuricemia
is a serum uric acid level greater than 6.8 mg/dl accompanied by joint pain and/or joint
inflammation or swelling. Meanwhile asymptomatic hyperuricemia, is defined as an serum
uric acid concentration of ≥ 6.8 mg/dl without prior gout flares or subcutaneous tophi.
Sputum culture conversion was defined as two consecutive negative cultures separated
by at least 30 days. The Outcomes claasified into recoverred, dropped put out, and died.
Data analysis was carried out by computerized using SPSS 25. Categorical data
were peresented in frequency distribution score (%). We analyzed these data with
correlation test coefficient contingency for nominal data and spearman rank for ordinal
data. P-value <0.05 was considered significant. The coefficient correlation used for

2
determining the strength of the correlation were very weak (0-0.2), weak (0.2-0.4),
moderate (0.4-0.6), strong (0.6-0.8), and very strong (0.8-1.0). The categorical data for
unpaired groups were tested for differences using the Chi square/Fisher exact test.

RESULTS
During the study period there 313 patients with DR-TB of these patients, 90 of them
experinced hyperuricemia comprising 58 subjects (64.4%) with asymptomatic
hyperuricemia and 32 subjects (35.6 %) with symptomatics hyperuricemia. Our analysis
revealed no significant difference between symptomatic and asymptomatic groups in
terms of age (P=0.804), sex (P=0.727), therapy regimen (P=0.801), uric acid level
(P=0.053), treatment initiation time (P=0.315), and sputum conversion time (P=0.784).
(Table 1)
Table 1. The demographic characteristics of the study subjects
Group
Characteristic p-value
Asymptomatic Symptomatic
N 58 (64.4%) 32 (35.6%) -
Age (Mean±SD) 42.43 ± 14.04 41.68 ± 12.69 0.804a
Sex 0.727b
Male 43 (47.8%) 21 (23.3%) -
Female 15 (16.7%) 11 (12.2%) -
Regimen 0.801b
All oral STR 30 (33.3%) 17 (18.9%) -
Kanamycin/amikacin-contain STR 16 (17.8%) 7 (7.8%) -
LTR 12 (13.3%) 8 (8.9%) -
a
Uric acid value 9.34 ± 2.50 10.44 ± 2.64 0.053
Treatment initiation time 16.81 ± 21,26 19.46 ± 42.89 0.315c
Sputum Convertion time 66.44 ± 26.87 69.03 ± 34.80 0.784c
Information : Categorical data with a nominal scale are displayed with percentage.
Numerical data mean and standard deviation (SD). b = Categorical data
for unpaired groups tested with Chi square/Fisher exact test. a =
Numerical data meeting the normality requirements for unpaired groups
are subjected to an independent t test. c = Numerical data that do not
meet the normality requirements in the unpaired group are subjected to
the Mann Whitney test. The normality test was carried out using the
Kolmogorov Smirnov test and the difference was declared significant if
the test yielded p <0.05.

Either symptomatic or asymptomatic hyperuricemia did not correlate with the outcomes of
DR TB patients (p=0.821). In addition, the very low correlation coefficient (0.024)
indicates a very weak correlation between the two variables suggesting that

3
hyperuricemia did not have a significant effect on the otucomes DR-TB patients. (Table
2).
Table 2. The Correlation of hyperuricemia types with the outcomes of DR-TB patients
Hyperuricemia Correlation
Outcome p-value
Asymptomatic Symptomatic Coefficient
Recovered 50 (55.6%) 27 (30.0%)
Drop out 3 (3.3%) 2 (2.2%) 0.821 0.024
Died 5 (5.6) 3 (3.3%)
Information: correlation test coefficient contingency (ordinal vs nominal); *
significant at p<0.05; ** significant at degree p<0.01.

In this study, patients who experienced hyperuricemia were classified into

asymptomatic and symptomatic based on DAIDS Table for Grading the Severity of Adult
and Pediatric Adverse Events 2017. (Table 3 and figure 1)

Table 3. Classification of hyperuricemia based on the degree of severity

Number (n) Percentage (%)
Grade 1 ( 7,5 – 10,0) 49 54.4
Grade 2 (10,0 – 27 30.0
12,0)
Grade 3 (12,0 – 10 11.1
15,0)
Grade 4 (> 15 4 4.4
Total 90 100.0

Figure 31. Classification of hyperuricemia based on the degree of severity

We found no significant differences regarding the outcomes of DR TB patients with

asymptomatic or symptomatic hyperuricemia receiving kamamycin/amikacin contain STR
(p-value 0.619), all oral STR (p-value 0.357), and LTR (p-value 0.255). The time of
sputum conversion among DR TB patients with asymptomatic and symptomatic
hyperuricemia administerde with kamamycin/amikacin contain STR (p-value 0.141), all

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oral STR (p-value 0.478), and LTR (p-value 0.938) was not signifantly difference. (Table
4).
Table 4. The comparison test between asymptomatic and symptomatic hyperuricemia
receiving DR-TB treatment in terms of outcomes and sputum convertion time
Hyperuricemia
p-value
Asymptomatic Symptomatic
All oral STR (n=30)
Outcome 0.357a
Healed 25 (53.2%) 15 (31.9%)
Drop out 3 (6.4%) 2 (4.3%)
died 2 (4.3%) 0 (0.0%)
Sputum convertion time 68.00 ± 25.47 70.05 ± 41.21 0.478b
Kanamycin/amikacin contain
STR (n= 16)
Outcome 0.619a
Healed 14 (60.9%) 7 (30.4%)
Drop out 1 (4.3%) 0 (0%)
died 1 (4.3%) 0 (%)
Sputum convertion time 62.13 ± 23.70 72.86 ± 24.93 0.141b
LTR ( n = 12)
Outcome 0.255a
Healed 11 (55.0%) 5 (25%)
Drop out 0 (0%) 0 (0%)
died 1 (5.0%) 3 (15%)
Sputum convertion time 68.33 ± 35.04 63.50 ± 29.95 0.938b
Information : a= Chi square/ Fisher exact test; b= Mann whitney test

DISCUSSION
Drug-resistant tuberculosis (DR-TB) is a significant global health concern, and its
treatment often involves the use of multiple drugs. Although these medications are
essential for managing the disease, they can also cause various side effects, including
hyperuricemia. Asymptomatic hyperuricemia is defined as abnormally high serum urate
level, without gouty arthritis or nephrolithiasis. Gouty arthritis typically occurs in patients
with hyperuricemia. Hyperuricemia predisposes patients to both gout and
7,8,9
nephrolithiasis.
Hyperuricemia occurring in our subjects was mostly asymptomatic hyperuricemia
type. We found no difference in uric acid level in both asymptomatic and symptomatic
hyperuricemia subjects. To date there have been no studies assessing the relationship
between symptomatic and asymptomatic hyperuricemia with sputum conversion time and
outcomes of DR-TB patients. Therefore this study may open new horizons regarding the
incidence of hyperuricemia in DR-TB treatment.10,11

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 The occurrence of side effects can be a significant factor in discontinuation of
anti-TB drug treatment. The level of patient adherence to treatment indicates the success
rate of TB treatment. Inadequate management of side effects and long-term use of drugs
may be some of the triggers for non-adherence to anti-TB drugs or even drug withdrawal.
Non-adherence to anti-TB drugs due to drug side effects will increase the risk of delayed
sputum conversion, continued transmission in the community, and treatment failure. 12
In this study, asymptomatic and symptomatic hyperuricemia were not associated
with sputum conversion time and outcome. There was no significant difference between
outcomes as well as sputum convertion time in DR TB patients with asymptomatic and
symptomatic hyperuricemia using the kamamycin/amikacin-contain STR, all oral STR and
LTR.
It is important to monitor for signs and symptoms of hyperuricemia, such as joint
pain, swelling, and rednessin patients receiving DR-TB treatment. If hyperuricemia is
severe or persistent, it may be necessary to adjust the dose or type of DR-TB medication
to reduce the risk of side effects.Overall, the management of hyperuricemia in patients
undergoing DR-TB treatment requires a multidisciplinary approach that involves close
monitoring, appropriate medication management, and lifestyle modifications. Healthcare
providers should work closely with patients to develop an individualized treatment plan
that takes into account their medical history, medication regimen, and other factors which
may affect their risk of developing hyperuricemia. 12,13

CONCLUSION
There were no differences in outcome and timing of sputum conversion in DR TB
patients either with asymptomatic and symptomatic hyperuricemia who received
kanamycin/amikacin-containing STR, all oral STR, and LTR.

6
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