The Corelation Between CD4+ T

ORIGINAL ARTICLE
The Corelation Between CD4+ T-lymphocyte Count
and Tuberculosis Form in TB-HIV Coinfected Patients
in Indonesia
Felix C. Fredy, Frans Liwang, Rudy Kurniawan, Anna Uyainah Z. Nasir
Department of Internal Medicine, Faculty of Medicine, University of Indonesia – Cipto Mangunkusumo Hospital.
Jl. Diponegoro no. 71, Jakarta Pusat, 10430, Indonesia. Correspondence mail: xilefchikita@hotmail.com.
ABSTRAK
Tujuan: untuk mengetahui apakah terdapat korelasi antara jumlah CD4+ dengan jenis TB pada pasien
TB-HIV di Indonesia. Metode: penelitian ini merupakan studi potong lintang dari pasien TB-HIV yang terdaftar
di POKDISUS, Rumah Sakit Cipto Mangunkusumo pada tahun 2008-2011. Peneliti membedakan jenis TB
menjadi TB paru, TB ekstraparu, dan TB miliar, dan jenis campuran. Data kemudian dianalisis dengan tes
korelasi Spearman dan Lambda. Peneliti juga melakukan uji korelasi parsial untuk mengeliminasi beberapa
faktor perancu, termasuk faktor demografi (umur, jenis kelamin, dan IMT) dan karakteristik klinis (derajat
klinis HIV, pulasan bakteri tahan asam, dan laju endap darah). Hasil: sebanyak 122 pasien TB-HIV (median
umur 31 [18-34], 80% laki-laki) tergabung dalam penelitian ini. Prevalensi jenis TB yang didapat adalah TB
paru (71%), TB esktraparu (7,4%), TB kombinasi (18,9%), dan TB milier (2,5%). Median jumlah CD4 adalah
40 sel/ml (RIK 17,5-100,6). Berdasarkan hasil analisis statistik, terdapat korelasi sangat lemah antara jumlah
CD4+ dengan jenis TB pada pasien TB-HIV di Indonesia (r=0,185, p=0,042). Faktor lain yang memiliki korelasi
adalah derajat klinis HIV (r=0,289; p=0,001). Setelah dilakukan penyesuaian terhadap berbagai faktor tersebut,
peneliti menemukan bahwa terdapat peningkatan korelasi antara jumlah CD4+ dengan jenis TB di Indonesia
(r=0,353; p=0,000). Kesimpulan: terdapat korelasi antara jumlah CD4+ dan jenis TB pada pasien TB-HIV di
Indonesia, tetapi merupakan korelasi yang sangat lemah.
Kata kunci: koinfeksi TB-HIV, jumlah CD4+, jenis TB.
ABSTRACT
Aim: to find whether there is a correlation between CD4+ count and TB form in TB-HIV Coinfected patients
in Indonesia. Methods: this is a cross-sectional study of the TB-HIV patients at National HIV Center POKDISUS,
Cipto Mangunkusumo Hospital in 2008-2011. We classified TB form as pulmonary TB, extrapulmonary TB,
milliary TB, and combination form. The data were analyzed by Spearman and lambda correlation test. We
also did partial correlation test to eliminate some counfounding factors, including demography and clinical
characteristics, that had been determinated before. Results: there were 122 TB-HIV patients (aged median
31 [18-34], 80% male) included in this study. The most common TB form was pulmonary TB (71.2%), then
extrapulmonary TB (7.4%), the combined type (18.9%), and milliary TB (2.5%). Median of CD4+ count was
40 cells/mL (IQR 17.5-100.6). There was a very weak correlation between CD4+ count and TB form in TB-HIV
patients in Indonesia (r=0.185; p=0.042). The other factor that also showed a significant correlation to TB form
is HIV staging (r=0.289; p=0.001). After adjusting those factors, we found an increase on correlation between
CD4+ count and TB form (r=0.353; p=0.000). Conclucion: there was a correlation between CD4+ count and
TB form in TB-HIV patients in Indonesia, but in a very weak correlation.
Key words: TB-HIV coinfection, CD4+ count, TB form.
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Acta Medica Indonesiana - The Indonesian Journal of Internal Medicine
Vol 44 • Number 2 • April 2012
The Correlation Between CD4+ T-lymphocyte Count and Tb Form
INTRODUCTION
Tuberculosis is the major leading opportunistic
infection and also the leading cause of death in
HIV patients. TB coinfected patients usually
have higher viral load, and more rapid decline
in immune status.1,2 However, TB and HIV
also have sinergic effects to human body. TB
could induce the macrophage to produce some
transcription factors (TNF α, IL-1, Il-6) with
the increasing of HIV replication rates. On the
other hand, HIV could lower the immune system
like CD4+ T-Lymphocyte and as a consequence,
the risk of TB opportunistic infection will also
increase with lack of immune response.3
Due to the defect in immune response, it
is difficult to identify TB manifestations in
TB-HIV patients, especially in advanced stage
HIV patients.3 The clinical manifestations of
TB in HIV patients are often unclear, such
as negative stainning sputum, atypical chest
x-ray pattern, and quite similar to the other
pulmonary opportunistic infections. Moreover,
the prevalence of extrapulmonary TB form at the
first diagnose is higher in TB-HIV patients.4 In
Cipto Mangunkusumo General Hospital, Jakarta,
2009, the number of TB-HIV patients are 175
patients, with 161 patients (92.0%) diagnosed
as pulmonary TB at the first visit and 14 patients
(18.0%) diagnosed as extrapulmonary TB.5 This
different form of TB is certainly very important
to be identified by clinician because of their
different treatment approach.
Based on the problem mentioned, the
immunity status of HIV patients, such as
CD4+ T-Lymphocyte count, is hypothesized
as a TB form predictor in TB-HIV patients.
Extrapulmonary or miliary TB are frequently
encountered in advanced HIV patients (CD4+
<200). We conduct this study to find the
correlation between CD4+ count and TB form in
high TB prevalence country, such as Indonesia.
We hypothesize that CD4+ count has a correlation
with the TB form in Indonesia.
METHODS
It was a cross-sectional study, using
secondary data from National HIV Center named
POKDISUS, Cipto Mangunkusumo Hospital,
Indonesia in 2008-2011. All the data has received
approval from the ethical committee for Medical
Research in Faculty of Medicine, University
of Indonesia, and we also have been obtained
permission to used the data from Pulmonology
Division, Department of Internal Medicine, Cipto
Mangunkusumo National Public Hospital.
Subjects included all TB-HIV coinfected
outpatients. We collected any demographical and
clinical data, such as age, sex, education level,
body mass index (BMI), mode of transmission,
acid fast bacilli (AFB), erythrocyte sedimentation
rate (ESR), TB form, category of TB treatment,
and CD4+ count. The subjects would be excluded
from the analysis if any characteristics data were
not complete.
The data were shown as mean, standard
deviation (SD), median and or range. According
to WHO classification for antiretroviral usage,
CD4+ count are categorized into three groups:
<200, 200-350, and >350 /mm3. The HIV staging
based on WHO clinical presentation was divided
into stage I, II, III, and IV. It is defined the TB
form as pulmonary TB, extrapulmonary TB,
combined pulmonary and extrapulmonary TB,
and milliary TB. Only two types of staining,
negative or positive were valid to be included
into this study.
Data were analyzed by bivariate correlation
lambda analysis and Spearman rank’s test for
each nominal and categorical data respectively.
Furthermore, partial correlation test was
conducted to find out the correlation between
CD4+ count and TB after adjusting other factors
that might be influenced. All data were processed
by SPSS 17.0.
RESULTS
The total 122 data of the TB-HIV coinfected
patients within 3 years were included in analysis.
Most subjects are male and in reproductive age.
In this study, drugs used is the main transmission
mode of HIV. None of the subjects are HIV stage
I and II. More than half of them are HIV stage
III while the remaining are stage IV. All TB form
can be found among the subjects, but the most
common is pulmonary TB, followed by combined
pulmonary and extrapulmonary, extrapulmonary,
and milliary TB. Median CD4+ count amount is
extremely low (Table 1).
Bivariate analysis was performed to identify
the correlation between CD4+ count and TB
form. A very weak correlation exists between
CD4+ count and TB form shows very low
123
Felix C. Fredy
Acta Med Indones-Indones J Intern Med
Table 1. Subject characteristics
Characteristics
Age (year) (median, IQR)
Subject (n=122)
31 (28-34)
Sex (n, %)
-- Male
101 (82.8)
-- Female
21 (17.2)
Education (n, %)
-- No education background
1 (0.8)
-- Elementary school
5 (4.1)
-- Junior high school
13 (10.7)
-- Senior high school
80 (65.6)
-- College
23 (18.8)
Body Mass Index (BMI)(Kg/m2)
(n, %)
-- Under weight
69 (56.6)
-- Normal
42 (34.4)
-- Over weight
5 (4.1)
-- Obese
6 (4.9)
Mode of transmission (n, %)
-- Sexual intercourse
31 (25.4)
-- Drugs user
70 (57.4)
-- Blood transmission
-- Others
0 (0.0)
21 (17.2)
Acid Fast Staining (n, %)
-- Positive
22 (18.0)
-- Negative
100 (82.0)
ESR (mean ± SD)
-- Stage I
0 (0.0)
-- Stage II
0 (0.0)
-- Stage III
72 (59.0)
-- Stage IV
50 (41.0)
TB form (n, %)
-- Extrapulmonary TB
-- Combined pulmonary and
extrapulmonary
-- Milliary
87 (71.2)
-- Category 2
CD4+ Count (median, IQR)
23 (18.9)
3 (2.5)
107 (87.7)
15 (12.3)
40 (17.5- 100.6)
correlation (r=0.185; p=0.042). This study
also did correlation test for other clinical and
demographic characteristics that might have
correlation with TB form. Among them, sex,
AFB, and HIV staging show a significant
correlation where sex and AFB show a very weak
124
r
p
CD4+ Count1
0.185
0.042
Age
–0.045
0.622
Sex2
0.000
0.000
BMI
–0.021
0.817
HIV Staging1
0.289
0.001
2
AFB
0.000
0.000
ESR1
0.064
0.481
1
1
1
2
Spearman’s Rank Correlation Test
Contingency Coefficient Lambda Test
Table 3. Partial correlation between CD4+ and TB form
r
p
Adjusted for HIV staging
0.333
0,000
Adjusted for demographical
characteristics (age, sex, BMI)
0.346
0,000
Adjusted for clinical characteristics
(HIV staging, AFB, ESR)
0.338
0,000
Adjusted for age, sex, BMI, staging,
AFB, ESR
0.369
0,000
9 (7.4)
Category of TB treatment (n, %)
-- Category 1
Table 2. Correlation between CD4+ count, age, sex, mode
of transmission, HIV staging, AFB, ESR, and TB form
(bivariate analysis)
77.3±32.5
HIV staging (n, %)
-- Pulmonary TB
correlation while HIV staging shows a weak
correlation. The others, including age, BMI, and
ESR, does not show any significant correlations
(Table 2).
The strength of correlation between CD4+
count and TB form increases when factors that
have a significant correlation in bivariate analysis
were adjusted (Table 3). However, it also was
seen when other clinical and demographic factors
were adjusted.
DISCUSSION
Subject Characteristics
As one of the countries in the world with the
highest TB prevalence, Indonesia may show a
different correlation between CD4+ count and
TB form, compared to other countries. HIV/
AIDS patients in Indonesia usually come to the
hospital after in advanced stage; therefore, we
found all subjects are in HIV stage III and IV
with the median of CD4+ count is 40 cells/μL.6-8
On the other hand, our data show the similar
characteristics to the national epidemiology data
that the main modes of transmission are sexual
intercourse and drug users. However, the quite
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The Correlation Between CD4+ T-lymphocyte Count and Tb Form
interesting fact is most of the subjects come
from well educated people instead of from low
educated people.9,10
TB-HIV in the High TB Prevalence Country
In this study, the correlation between CD4+
and TB forms is significant, but very weak. This
finding is different from other previous studies in
several countries due to the different prevalence
of TB. In the countries with low prevalence of
TB, most of the patients are elderly population
due to reactivation of latent infection. However,
that mechanism will be different in other
countries with higher TB transmission or stable
for many years, such as Indonesia. TB cases are
more likely found in young adults population
because of recent infection or reinfection.10-12 A
study in Isparta showed that the severity forms of
TB, such as extrapulmonary TB, increase steadily
with age.11 It can be predicted that TB has greater
chance to become more severe or extrapulmonary
form in Indonesian.
It is clear that not all of the TB infection
will manifest as TB illness. However, only 70%
will become primary TB. In several conditions,
this pathogenesis will lead to pulmonary TB,
extrapulmonary TB, or latent TB infected (LTBI).
The probabilities of those TB forms will be
different in TB-HIV patients. At the time people
infected by HIV in which the CD4+ count is high,
TB can be already in any forms. When the HIV
starts lowering immune system, the primary TB
can be easily transformed to progressive primary
TB and extrapulmonary TB. In the others who
have already had extrapulmonary TB, it will
still remain extrapulmonary TB or even become
combined TB form. In these cases, CD4+ fails
to predict the severity of TB.
Cellular Response in Coinfected TB-HIV
Patients
For immunocompromised infected people,
TB granuloma formation is unsuccessfully
initiated in containing the bacilli. The necrotic
tissue undergoes liquefaction, and the fibrous
wall loses structural integrity. The semiliquid
necrotic material can then drain into a bronchus or
nearby blood vessel, leaving an air-filled cavity at
the original site becoming extrapulmonary TB.13
Investigators have shown that M tuberculosis
can also increase viral replication in infected T
lymphocytes and monocytes in HIV patients.
A recent study demonstrated a 5- to 160-fold
increase in viral replication during the acute
phase of untreated tuberculosis. The clinical
significance of this increase in viral load is
uncertain. Moreover, high levels of tumor
necrosis factor (TNF)-α, which is known to
increase HIV replication and viremia, have
been demonstrated in both HIV-seropositive
and -seronegative tuberculosis cases.14 Besides,
IFN-γ production is decreased in parallel with
reduction in CD4+ cells, leading to increased risk
of reactivation of or infection with tuberculosis.15
Based on these findings, HIV infected people
will be more vulnerable to get TB infection. In
addition, the TB infection is more progressive.
As a result, TB-HIV infected people could have
more severe TB although the CD4+ count, its
immune system, is still high. It explains why in
our study we did not find any correlation between
CD4+ and TB form.
TB Form and Affecting Factors
In order to figure out the confounding factors,
we did correlation analysis between demographic
and clinical characteristics with TB form. Those
characteristics include age, sex, BMI, staining,
and ESR.
According to Rodwell et al, foreign-born
TB–HIV coinfected individuals are reported to
be in the United States for an average of 13,1
years before being diagnosed, which was not
significantly different (p=0.346) from individuals
in the TB–HIV negative group (14.0 years) and
TB–HIV unknown group (18.0 years).16
Study conducted by Forssbohm shows
that females were more likely than males to
have extrapulmonary TB in all countries, and
in virtually every age group. The reason is not
clearly explained, but it suggests that endocrine
factors might play a role.17,18
BMI could indirectly describe human
imunity function which influence the progress
of the disease. In many publication before, TBHIV patients have BMI lower than TB or HIV
significantly. Moreover, lower BMI could become
strong predictor to HIV patients mortality.19,20
According to previous studies, there is no
correlation between CD4+ count and the staging
of HIV patients. It only shows that the decreasing
of CD4+ count is followed by increasing the
viral load. However, in TB-HIV Coinfected
patients, this correlation was not clear. There is
a dissociation between immunological and HIV
125
Felix C. Fredy
virological markers, even the staging of HIV
patients.19,21-23
Smear-negative TB occurs more frequently
in HIV-infected patients compared to the general
population. However, Shea, et al already proved
that acid-fast staining is still sensitive and specific
for diagnosis TB in an African population with
high prevalence of HIV. HIV positive is more
likely found in acid fast staining with a large
number of bacilli (+2 and +3).24,25
The role of erythrocyte sedimentation
rate (ESR) in monitoring HIV/AIDS is still
controversial.26 A study in South Africa shows
that 76% ESR 100 and above are HIV-positive
patients.27 Furthermore, a study conducted by
Ndakotsu concluded TB-HIV patients and people
with low CD4+ count had ESR higher than
asymptomatic patients.28 Indeed a elevated ESR
may have a relation with clinical and immune
status in HIV infected patients.
After adjusting those factors, we did not find
any significant improvements in CD4+ count
and TB form correlation. We assume there are
other factors that affect TB manifestation in HIV
infected people.
Although this study can represent the typical
HIV/AIDS patients in Indonesia, it still can not
cover all patients because of limitation in case
finding. Subjects are the patients from national
referral hospital. Another limitation is the limited
sample size included in analysis. It is much
better if the onset of TB and HIV be known. The
causative analysis can be done if these data are
provided.
CONCLUSION
TB still becomes the main coinfection
in HIV patients. It has uncertain clinical
manifestations, unclear diagnosed, including the
routine laboratory examinations. CD4+ count as
one of laboratory testing generally conducted in
HIV patients, often considered by physicians as
predictor of TB form. It will reduce their concern
while the patient has high level of CD4+ count. In
fact, there is very low correlation between them.
Hopefully the physicians should be aware
of TB in all its clinical staging, not only using
CD4+ count as the predictor of the severity of
TB in TB-HIV patients. As we treat the patients
comprehensively, there are many other factors
that influence the forms of TB. Hence, it is
126
Acta Med Indones-Indones J Intern Med
needed to conduct other research to get more
specific issues.
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