Effect of Body Weight on Cytokine Response to Anti-tubercular Therapy in Patients with HIV Infection and Tuberculosis
Ivaturi Venkata Nagesh1*, Sashindran VK2, Anurag Sonkhle3
1 Professor (Internal Medicine), MH Ambala, Haryana, India.
2 Professor and Consultant (Internal Medicine & Infectious Diseases), Principal Medical Officer, Central Air Command, Prayagraj, Uttar Pradesh, India.
3 Resident(Internal Medicine), AFMC, Pune, India.
*Corresponding Author
Dr. Ivaturi Venkata Nagesh,
Professor (Internal Medicine), MH Ambala, Haryana, India.
Tel: +919618024173
Fax: 01712974173
E-mail: ivaturi_venkata@rediffmail.com
Received: October 22, 2020; Accepted: November 03, 2020; Published: November 09, 2020
Citation: Ivaturi Venkata Nagesh, Sashindran VK, Anurag Sonkhle. Effect of Body Weight on Cytokine Response to Anti-tubercular Therapy in Patients with HIV Infection and Tuberculosis. Int J AIDS Res. 2020;7(1):196-199. doi: dx.doi.org/10.19070/2379-1586-2000037
Copyright: Ivaturi Venkata Nagesh© 2020. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
Abstract
Introduction: Nutrition plays an important role in stimulating the immune response to varied pathogens especially in patients
with tuberculosis. Cytokine response to antitubercular therapy is highly variable in patients with HIV infection and Nutrition plays
an important role in determining this response.
Objectives: To study the effect of body mass index in the levels of cytokines IL-10, IP-10, IL-4 and Interferon- Gamma before
and after treatment with anti tuber-cular therapy in patients with HIV infection.
Material and methods: It is a prospective cross sectional study , with a population of 50 individuals with HIV infection with tuberculosis
were studied.
Results: The mean levels of cytokines IFN-Gamma, IP-10, IL-10 and IL-4 in low BMI group before initiation of ATT are
72.62U/l, 8.90pg/ml, 26pg/ml and 1.24pg/ml. The levels after completion of 02 months of ATT are 17.10, 4.56 , 9.14 and 0.57
respectively.
The mean levels of cytokines IFN-Gamma, IP-10, IL-10 and IL-4 in normal BMI group before initiation of ATT are 22.32, 4.17,
11.25 and 0.78. The levels after completion of 02 months of ATT are 17.10, 4.56 , 9.14 and 0.57 respectively.
Conclusions: BMI as surrogate marker for nutrition pals an important role in cytokine response. The change in levels of Interferon
- gamma in low BMI group were statistically significant.
2.Abbreviations
3.Introduction
4.AIDS Demographics in Bangladesh
4.1 Transmission into Bangladesh
4.2 Prevalence of AIDS associated diseases in Bangladesh
4.3 Alarming recent trend of HIV in Bangladesh
4.4 Treatment facilities in Bangladesh
4.5 Risk Groups
4.6 Dealing with HIV/AIDS
4.7 Factors that contribute to HIV prevalence in Bangladesh
5.Changing the Scenario
5.1 Key Challenges
5.2 4th National Strategic Plan to End AIDS by 2030
6.Future Direction
7.References
Keywords
Cytokines; Tuberculosis; HIV Infection, Body Mass Index.
Introduction
Tuberculosis is one of the major public health issues across the
world and remains the leading cause of death worldwide. Tuberculosis
is the commonest opportunistic infection in people with
HIV/AIDS and the combination is lethal. According to WHO
Report 2018, about 2,51,000 people died of HIV-associated TB
(HIV-TB). In 2018, there were an estimated 8,62,000 new cases
of TB amongst people who were HIV-positive [1]. India accounts
for about 10% of the global burden of HIV-TB.
Nutrition has a vital role in the immune functions of an individual.
HIV-TB is known to cause wasting in the patients. WHO
recognises Tuberculosis and HIV to be associated with caloric,
protein malnutrition, micronutrients deficits and recommends the
patients with mild or moderate malnutrition to eat a healthy diet
that meets th Recommended Dietary Allowance (RDA) [2].
Malnutrition, as indicated by body mass index (BMI), is the leading
cause of sec-ondary immune deficiency and is known to have
a direct effect on T- Lymphocyte response. It is also associated
with reduced cytokine response. The level of circulat-ing pro-inflammatory
cytokines are reduced whereas the level of regulatory
cytokines are increased in an individual with the low nutritional
status [3]. Many animal studies have shown that malnutrition has
a detrimental effect on host immunity against infection. Lack of
proteins and other nutrients in the diet causes thymic atrophy
and impairs generation, maturation and function of T - Lymphocytes.
Protein deficiency also impairs sequestration of reactive T
lymphocytes thereby causing loss of tuberculosis resistance and also makes the monocytes macrophages to produce TGF – β,
known as a mediator of immunosuppression in tuberculosis [4].
The role of nutrition in cytokine response of an individual suffering
from HIV-TB is compounded by the direct effect of HIV
on the cytokine levels. HIV infection leads to a chronic inflammatory
state and is associated with increase in levels of proinflammatory
cytokine like IFN γ and reduced levels of IL-6. Whereas
on the other hand malnutrition blunts the immune inflammatory
response as characterized by reduced levels of pro-inflammatory
cytokines like IFN γ and raised levels of IL-6 and IL-4 [8]. Th1
cytokines required for Th1 differentiation (IL-7, IL-12, IL-18 and
IL-21) and function (IL-2 and IFN-γ) are reduced in peripheral
blood mononuclear cells of children with malnutrition and severe
infection. In the same children, an overexpression of Th2
cytokines (IL-4 and IL-10) and increased apoptosis of CD3+ T
cells is noted [9]. Hence we planned to study the effect of body
mass index on two pro-inflammatory cytokines i.e interferongamma(
IFN -γ), and interferon gamma inducing protein -10 (IP-
10), and two anti-inflammatory cytokines: interleukin-4(IL-4) and
interleukin-10(IL-10).
Aim: To assess the role of malnutrition on the cytokine response
to anti -tubercular therapy (ATT) in HIV-TB.
Aim: To assess the role of malnutrition on the cytokine response
to anti -tubercular therapy (ATT) in HIV-TB.
Objectives:
1) To assess the effect of BMI on cytokine levels prior to starting
ATT.
2) To assess the effect of BMI on cytokine levels after intensive
phase of ATT.
3) To determine if nutritional status has a role in cytokine response
to ATT (i.e. change in levels).
Material and Methods
In this prospective pilot study all consenting patients of HIV-TB
with either fresh pulmonary/extra-pulmonary TB being started
on ATT were enrolled. Over the study duration 50 patients were
enrolled and followed till the completion of intensive phase (IP)
of ATT (i.e. for 2 months). The exclusion criteria were as follows:
- Patients on long- term steroids
- History of diabetes mellitus, rheumatological disorders
- Past history of tuberculosis
- Patients with chronic kidney disease
- Patients with acute viral infection (other than HIV)
- Patients with haematological malignancy
- Pregnancy
- Other opportunistic infections in patients with HIV infection
Serum cytokine levels of IL-4, IL-10, IP-10 and IFN– γ were estimated
by ELISA, at the start of therapy (or within 02 weeks of
initiation of ATT) and after 02 months of therapy.
Serum concentrations of IFN-γ, IL-4, IP-10 and IL-10 were determined
by commercial ELISA kits (human IFN-γ, IL-4, and
IL-10, IP-10) high sensitivity ELISA kits, Gen-Probe Diclone, France. All tests were performed in duplicate.
The statistical analysis of results was done by IBM SPSS statistics
22 software, and scatter plot along with linear regression analysis
was done using statsmodels package in Python 3.7.
Results
The study was conducted on 50 patients with HIV-TB commencing
ATT. Out of 50 patients, 43 were male and 7 were female. The
average age was 39.42 years ± 12.72 (SD). The mean duration of
HIV illness was 2.4 years. The mean weight of the subjects was
57.10 kg ± 11.07 (SD). The mean values of haemoglobin (Hb),
erythrocyte sedimentation rate (ESR) and CD4 cell count were
10.53 gm/dl ± 1.65 (SD), 47.28 mm fall in 1st hr ± 18.93 (SD)
and 341.76 cells/cmm respectively. Body Mass Index (BMI), the
surrogate marker for malnutrition, was calculated and the patients
were divided into three groups, individuals who were malnourished
as reflected by low BMI (<18.5 kg/m2), individuals who
had normal nourishment status as reflected by normal BMI (18.5-
24.9 kg/m2) and individuals who were found to be overweight or
obese during the study as indicated by BMI (>24.9 kg/m2). Out
of 50 patients 15 were underweight (BMI <18.5), 30 were with
normal BMI (BMI 18.5 - 24.9) and 5 patients were overweight
(BMI >25.0 kg/m2). The mean Hb level among this group was
9.14 g/dL, indicative of anaemia in these patients. The mean Hb
of subjects with BMI >18.5kg/m2 was 11.09 gm/dl which was
higher as compared to the low BMI group. The mean cytokine
values both pre-ATT and post-IP with respect to BMI are shown
in Table 1 below.
Table 1.
The log cytokine levels were analysed before and after the intensive phase of ATT and paired ’T’ test was performed. The values are shown in Table 2 below:
Table 2.
In order to analyse the effect of BMI on the cytokine levels, both at baseline and after the IP, BMI was considered as a continuous variable and multivariate linear regression analysis was done with BMI and treatment status (i.e. pre-ATT and post-IP). Strata scatter plot with overlying regression for all the cytokines is given in Figures 1- 4.
Figure 1-4.
Linear regression analysis of log cytokines with time and BMI revealed log IP10 is inversely related to BMI and log IFN gamma significantly decreased after treatment as given in Table 3.
Table 3.
Discussion
Nutrition is an important component of treatment protocol in
various acute and chronic medical ailments [10]. Various studies
have revealed that malnutrition causes atrophic changes in the
thymus gland resulting in sub-optimal T-cell proliferation and
leading to secondary immunodeficiency [5, 9]. HIV infection further
impairs cell-mediated immunity and down-regulates immune
response thereby predisposing these patients to many opportunistic
infections [6].
As BMI has been taken as surrogate marker of nutrition in our
study, the role of the nutrition cannot be overlooked in popula tion with poor nutritional status and low CD4 count. Lonnorth et.
al [13] demonstrated that BMI is a reliable marker for nutritional
status and there is 14% decrease in incidence of Tuberculosis with
one unit rise in BMI. Leung that low BMI increases TB burden
[14] and low BMI is associated with decrease in proinflammtory
cytokines [11]. It has been demonstrated that immune response
in individuals with low BMI is down regulated. The same is manifested
in form of elevated levels of regulatory cytokines and reduced
levels of pro-inflammatory cytokines, thereby increasing
the susceptibility to acquisition of new infection and promoting
disseminated disease in affected individuals [13].
In our study there were more no.of low BMI patients than normal.
It is comparable to the study done by villamor [7] made who found similar results of more no. of malnourished indi-viduals
than normal BMI patients in comparison to other countries. In
our study we found the levels of pro inflammatory cytokines
(IFN-gamma and IP-10) were high in low BMI group than that of
normal BMI groups prior to initiation of ATT which is variance
with other studies by Anuradha et al., [10, 11]. The reason may
be due to other factors like higher disease burden of HIV and
concomitant low CD4 counts which dominated over nutrition per
se. The levels of anti inflammatory cytokine IL-10 levels were
high in low BMI group than normal BMI group which is consistent
with various studies [6, 7]. The decreased IL-10 levels may
lead to down regulation of initial inflammatory response thereby
promoting higher disease burden and disseminated disease as
compared to individuals with normal BMI [7] . The low level of
anti inflammatory cytokine levels may also due to HIV infection
per se which is by nature chronic inflammatory condition leading
to elevated levels of pro inflammatory cytokines and hence
the higher levels of pro inflammatory cytokine levels despite low
BMI are attributed to the same [9]. Our study revealed that the
level of anti inflammatory cytokines IL-10 and IL-4 both at the
baseline and after two months of ATT therapy are slightly higher
than that of individuals with normal BMI. The levels of Interferon
γ levels were reduced from initial stage to 02 months after
ATT therapy which was statistically significant, as was observed
in linear regression analysis, similar to study done by Azzuri [15]
but is in variance to study by Riou et. al [16]. However Riou et
al measured Interferon γlevels after 6 months of ATT, that too
in HIV negative individuals. Since ,most of our patients are on
HAART the results were different because of decrease of viral
load. A study by Mihret [17] found no significant change in levels
of Interferon gamma or any other cytokine levels after treatment
in HIV positive individuals. In our study the IP-10 levels
were not reduced significantly after 02 months of anti tubercular
therapy similar to the results by Mave [18] who noticed that the
chemokine levels IP-10 were decreased only after 48 weeks of
Anti retroviral therapy.
Logical aggression analysis revealed Log IP-10 values are inversely
related to BMI in response to anti tubercular therapy in contrast
to study by Azuri et.al [15] may be due to poor nutrition related
to low level of pro inflammatory cytokine. In our study none of
the anti inflammatory cytokines (IL-4, IL-10) showed a significant
change before and after treatment simiilar to result by Mihret.
However Siwaya et.al [19] found the levels of anti inflammatory
cytokines low before initiation of treatment. This finding may
suggest that in dually infected subjects, the HIV-related changes
dominate the overall immunological pic-ture and leads to dysregulation
of cytokine and chemokine production.
Conclusion
In our study anti inflammatory cytokines IL- 10 and IL-4 at the
baseline as well as after two months of ATT therapy are slightly
higher than that of individuals with nor-mal BMI. Interferon
γ levels were reduced from initial stage to 02 months of ATT
therapy. This study demonstrated BMI plays an important role
in change in the le-vels of cytokines which need larger studies to
corroborate the findings.
Acknowledgement
We are grateful to Col Suman Kumar Pramanik, Professor Medicine
and Haematology, Army Hospital (RR) New Delhi110010
for the statistical analysis of data.
References
- Tuberculosis (TB) [Internet]. Who.int. 2020 [cited 26 March 2020]. Available: https://www.who.int/news-room/fact-sheets/detail/tuberculosis.
- WHO. Guideline: nutritional care and support for patients with tuberculosis. 2013.
- Rajamanickam A, Saravanan Munisankar, Yukthi Bhootra, Nathalla Pavan Kumar, Chandrakumar Dolla, Paul Kumaran, et al. Coexistent Malnutrition is associated with Pertubations in Systemic and Antigen – Specific Cytokine Responses in Latent Tuberculosis Infection. Clinical and Vaccine Immunology 2016; 23(4): 339-345. PMID: 26865593.
- Dai G, McMurray DN. Altered cytokine production and impaired antimycobacterial immunity in protein - malnourished guinea pigs. Infect Immun. 1998; 66: 3562 – 3568. PMID: 9673234.
- Savino W. The thymus gland is a target in malnutrition. Eur J Clin Nutr. 2002; 56(3): S46-49. PMID: 12142962.
- McMurray DN. Cellular immune changes in undernourished children. Prog Clin Biol Res. 1981; 67: 305–318.
- Villamor E, Saathoff E, Mugusi F, Bosch RJ, Urassa W, Fawzi WW. Wasting and body composition of adults with pulmonary tuberculosis in relation to HIV-1 co-infection, socio-economic status, and severity of tuberculosis. Eur J Clin Nutr. 2006; 60(2): 163–171. PMID: 16234841.
- De Milito A. B lymphocyte dysfunctions in HIV infection. Current HIV Research. 2004; 2(1):11–21. PMID: 15053337.
- Sashindran VK, Thakur R. Malnutrition in HIV/AIDS: Aetiopathogenesis. InNutrition and HIV/AIDS-Implication for Treatment, Prevention and Cure 2020 Feb 20. Intech Open.
- Anuradha R, Munisankar S, Bhootra Y, Kumar NP, Dolla C, Kumaran P, et al. Coexistent malnutrition is associated with perturbations in systemic and antigen-specific cytokine responses in latent tuberculosis infection. Clin Vaccine Immunol. 2016; 23:339–345. PMID: 26865593.
- Anuradha R, Munisankar S, Bhootra Y, Dolla C, Kumaran P, Babu S. High body mass index is associated with heightened systemic and mycobacterial antigen specific pro-inflammatory cytokines in latent tuberculosis. Tuberculosis. 2016; 101: 56–61. PMID: 27865399.
- Chandrasekaran P, Saravanan N, Bethunaickan R, Tripathy S. Malnutrition: Modulator of Immune Responses in Tuberculosis. Front. Immunol. 2017; 8: 1316. PMID: 29093710.
- Lonnroth K, Williams BG, Cegielski P, Dye C. A consistent log-linear relationship between tuberculosis incidence and body mass index. Int J Epidemiol. 2010; 39(1): 149-55. PMID: 19820104.
- Leung CC, Lam TH, Chan WM, Yew WW, Ho KS, Leung G, et al. Lower risk of tuberculosis in obesity. Arch Intern Med 2007; 167(2): 1297–1304. PMID: 17592104.
- Azzurri A, Sow OY, Amedei A, Bah B, Diallo S, Peri G, et al. IFN-gammainducible protein 10 and pentraxin 3 plasma levels are tools for monitoring inflammation and disease activity in Mycobacterium tuberculosis infection. Microbes Infect. 2005; 7(1): 1-8. PMID: 15716076.
- Riou C, Perez Peixoto B, Roberts L, Ronacher K, Walzl G, Manca C, et al. Effect of standard tuberculosis treatment on plasma cytokine levels in patients with active pulmonary tuberculosis. PLoS One. 2012; 7(5): e36886. PMID: 22606304.
- Mihret A, Abebe M, Bekele Y, Aseffa A, Walzl G, Howe R. Impact of HIV co-infection on plasma level of cytokines and chemokines of pulmonary tuberculosis patients. BMC Infect Dis. 2014; 14: 125. PMID: 24592945.
- Mave V, Erlandson KM, Gupte N, Ashwin Balagopal, David M Asmuth, Thomas B Campbell, et al. Inflammation and Change in Body Weight With Antiretroviral Therapy Initiation in a Multinational Cohort of HIV-Infected Adults. J Infect Dis. 2016; 214(1): 65–72. PMID: 26962236.
- Siawaya J, Beyers N, van Helden P, G Walzl. Differential cytokine secretion and early treatment response in patients with pulmonary tuberculosis. J Infect Dis. 2009, 156: 69-77. PMID: 19196252.
