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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 10  |  Issue : 2  |  Page : 99-104

Correlation between serum lipid fractions and radiological severity in patients with drug-resistant pulmonary tuberculosis: A cross-sectional pilot study


1 Department of General Medicine, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India
2 Department of Pharmacology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India
3 Department of Radiodiagnosis, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India

Date of Submission06-Jan-2019
Date of Decision16-Mar-2019
Date of Acceptance25-Mar-2019
Date of Web Publication24-May-2019

Correspondence Address:
Dr. Manel Arjun Nayak
Department of General Medicine, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka - 575 001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/INJMS.INJMS_1_19

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  Abstract 


Background: We aimed to determine if serum cholesterol and body mass index (BMI), which are important in maintaining immunity, have any impact on the radiological severity in patients with drug-resistant pulmonary tuberculosis (DR-TB). Materials and Methods: A cross-sectional pilot study was conducted over 2 years in adults with newly diagnosed DR-TB. The radiological severity of the disease was determined using a chest X-ray (CXR) scoring formula. Correlation between the lipid fraction levels, BMI, and the CXR scores was determined using Pearson's correlation coefficient. Results: Thirty-three patients were included in the study. A significant negative correlation was seen between the CXR severity scores and total cholesterol (r = −0.546,P = 0.001), high-density lipoprotein-cholesterol (r = −0.479,P = 0.005), low-density lipoprotein-cholesterol (r = −0.431,P = 0.012), and BMI (r = −0.352,P = 0.044). Conclusions: Low serum cholesterol levels and low BMI were associated with an increased radiological severity which, in turn, could result in increased infectivity. Adequate nutritional supplementation in the diet of patients to increase BMI, and serum cholesterol levels, could potentially decrease the severity, and also consequently, transmission, and incidence of DR-TB.

Keywords: Cholesterol, drug-resistant tuberculosis, infection transmission, radiography


How to cite this article:
Nawaz A, Nayak MA, Hameer ST, Kamath A, Mahale A. Correlation between serum lipid fractions and radiological severity in patients with drug-resistant pulmonary tuberculosis: A cross-sectional pilot study. Indian J Med Spec 2019;10:99-104

How to cite this URL:
Nawaz A, Nayak MA, Hameer ST, Kamath A, Mahale A. Correlation between serum lipid fractions and radiological severity in patients with drug-resistant pulmonary tuberculosis: A cross-sectional pilot study. Indian J Med Spec [serial online] 2019 [cited 2019 Jun 26];10:99-104. Available from: http://www.ijms.in/text.asp?2019/10/2/99/258982




  Introduction Top


India accounts for one-fourth of the global tuberculosis (TB) burden. Based on the estimates reported in the Global TB Report 2016, an estimated 1.3 lakh incident drug-resistant TB (DR-TB) patients emerge annually in India.[1] Until recently, it was believed that most cases of DR-TB were due to improperly treated cases of drug-sensitive TB. However, epidemiological studies have shown that almost 95.9% of new DR-TB cases in new TB cases and 61.3% of DR-TB in previously treated cases are predominantly caused by person-to-person transmission.[2]

Cell-mediated immunity plays a key role in containing the spread of TB, and a slow lymphocytic response is one of the factors responsible for the spread of the infection.[3] Cholesterol plays a distinct role in the maintenance of the cell membrane structure because of its rigid ring.[4] Various studies have shown the importance of cholesterol in the maintenance of cellular immunity and the potential destructive effects of low cholesterol levels on the lymphocytes.[5],[6] Hence, it is possible that the serum cholesterol levels could have an impact on the severity of the infection which could possibly be reflected on the chest radiogram.

Chest radiography is one of the main investigations in the workup of patients with TB. Other than grading the sputum smear after acid-fast staining for Mycobacterium tuberculosis, chest radiography is possibly the only direct investigation available which can grade the severity of the infection. The severity on chest radiography has been shown to correlate positively with the severity grade determined by sputum smear examination.[7] Ascertaining the severity of the disease is important as those patients with a more severe disease are more likely to transmit it.[8],[9] Earlier studies have shown a negative correlation between the radiological severity and the various lipid fractions in drug-sensitive pulmonary TB.[10],[11] A statistically significant positive correlation has been demonstrated between total cholesterol (TC) level and the body mass index (BMI).[12] In addition, because protein–calorie malnutrition is directly linked to the risk of acquiring TB infection,[13] and BMI is an important measure of the nutritional status of an individual.[14] BMI calculation is an important parameter in the assessment of DR-TB patients.

As patients with DR-TB tend to have a more severe disease radiologically, when compared to patients with drug-sensitive TB (DS-TB),[15] and may not have adequate nutritional support, partly due to a lack of concrete measures in the Programmatic Management of Drug-Resistant Tuberculosis (PMDT),[16] we considered it important to have data which would add to previously done research in patients with DS-TB; whether the disease severity can be assessed based on serum lipid fraction measurement needs to be established in patients with DR-TB. A study showed that serum lipid levels were lower in patients with active pulmonary TB compared to their own household contacts.[17] Considering the above observations, we aimed to investigate the relationship between serum lipid fractions, BMI, and the radiological severity measured using chest radiography in patients with newly diagnosed DR-TB.


  Materials and Methods Top


This was a cross-sectional pilot study conducted at a DR-TB treatment center of a tertiary care teaching hospital. Patients with newly diagnosed DR-TB, resistant to both isoniazid and rifampicin, with or without resistance to other anti-TB drugs, were enrolled into the study between September 2015 and September 2017. All the patients were initially admitted for pretreatment evaluation and treatment initiation as per the PMDT guidelines, 2012.[16] A TB patient whose sputum is culture positive for M. tuberculosis and is resistantin vitro to isoniazid and rifampicin with or without other antitubercular drugs based on drug sensitivity testing (DST) results from an Revised National Tuberculosis Control Programme (RNTCP)-certified culture and DST laboratory is defined as a case of multidrug-resistant (MDR)-TB.[16]

Because this was a single-center study and a limited number of newly diagnosed DR-TB patients present to the center, no formal sample size calculation was made; all eligible patients who presented to the center during the study period were enrolled. The study was approved by the Institutional Ethics Committee, Kasturba Medical College, Mangalore (IEC KMC MLR 09-15/174), and a written informed consent was obtained from the participants.

DR-TB patients ≥ 18 years of age whose sputum was positive for acid-fast bacilli (Ziehl–Neelsen stain), had a documented normal chest radiogram previously, and consented to participate in the study were included. We also included age- and gender-matched healthy individuals who presented for routine checkup with a normal chest radiogram and no known disease for comparison of the serum lipid fractions. Basic medical history was obtained, and physical examination and blood investigations were performed to exclude patients with known extensively drug-resistant TB, human immunodeficiency virus infection, diabetes mellitus, hypertension, chronic kidney disease, chronic liver disease, hypothyroidism, acute or chronic pancreatitis, those with known primary hyperlipidemias, and those on medications (statins, fibrates, niacin, aspirin, beta-blockers, prednisolone, amiodarone, and diuretics) which could alter the lipid profile.

A fasting serum lipid profile (venous sample), which included TC, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), very LDL-C (VLDL-C), and triglycerides (TGs), was obtained at the time of admission, before the initiation of treatment. A fasting lipid profile was also obtained for the control group.

Rifampicin resistance was detected by Cartridge-Based Nucleic Acid Amplification Testing[16] using Gene Xpert IV (Cepheid, CA, USA), and isoniazid resistance was detected by line probe assay[16] (hybridization using GT-blot 48, Twincubator from Hain LifeScience, Nehren, Germany, and polymerase chain reaction using Mastercycler Nexus by Eppendorf, Hamburg, Germany) of the sputum samples. The above tests were done at the RNTCP-certified laboratories affiliated to the Drug-Resistant Tuberculosis Centre, and the sputum was also sent for liquid culture to detect resistance to other anti-TB drugs. Sputum culture was done by liquid culture medium using BD Bactec MGIT 960 system (Becton, Dickinson and company, BD India Pvt., Ltd., Haryana, India) at the State Intermediate Reference Laboratory at Hubli, Karnataka. A standard chest radiogram (posteroanterior view) was also obtained at the time of admission, before initiation of treatment. The radiography findings were recorded, and the radiological severity was assessed using a chest X-ray (CXR) score as described by Ralph et al.[7] The CXR score is calculated as follows:

CXR score =Proportion of the total lung affected (by any pathology) in % + 40% if cavitation present.

A higher CXR score indicates more severe disease. The CXR score obtained was further classified into three groups as follows: Group 1, CXR score <25%; Group 2, CXR score 25%–50%; and Group 3, CXR score >50%. The chest radiographs were independently assessed by two physicians and a radiologist. Any difference in the CXR scores was resolved by consensus.

In addition, the height (in meters) and weight (in kilograms) of the patients were recorded to calculate the BMI (weight [kg]/height [m2]). Blood investigations done included hemoglobin, total leukocyte and platelet count, blood urea and serum creatinine, liver enzymes, total bilirubin, and serum albumin. Hemoglobin was analyzed by the photometric principle; total leukocyte and platelet count was performed using UniCel DxH 800, Beckman Coulter (Miami, Florida, USA). TC was analyzed by cholesterol oxidase phenol 4-aminoantipyrine peroxidase, HDL-C by direct enzymatic method, LDL-C by direct determination, VLDL by calculation, TG by glycerine phosphate oxidase peroxidase, blood urea by urease glutamate dehydrogenase, serum creatinine by Jaffe colorimetry, total bilirubin by 3,5-dichlorophenyldiazonium tetrafluoroborate method, serum albumin by bromocresol green method, serum aspartate transaminase and alanine aminotransferase by ultraviolet kinetic, serum alkaline phosphatase by para-nitrophenol-colorimetry, all of the above using Roche Cobas 6000 (Indianapolis, USA).

Statistical analysis

The continuous variables were compared using Student's t-test. The normality of data distribution was confirmed using the Kolmogorov–Smirnov test with Lilliefors significance correction (P > 0.05). The correlation between the serum lipid fractions and radiological severity was determined using Pearson's correlation followed by partial correlation to control for age, BMI, hemoglobin, total proteins, and serum creatinine. A backward regression analysis was also performed using age, BMI, and the laboratory parameters as the variables to determine the parameters that best predicted the CXR scores. P < 0.05 was considered statistically significant. All the statistical analyses were performed using Statistical Package for the Social Sciences version 11.5 (SPSS Inc., Chicago, IL, USA).


  Results Top


Thirty-three patients with newly diagnosed DR-TB were enrolled in the study. Of these, 16 had previously been treated successfully for pulmonary TB (culture negative and chest radiogram was normal at the time of treatment cessation) and presented again with features of pulmonary TB and on evaluation, were found to have drug resistance; these patients' are considered to be “relapsed” cases of TB albeit with new evidence of drug resistance. At the time of enrollment, these patients had not been on anti-TB medications for at least the past 6 months. The remaining 17 patients had never been diagnosed with TB earlier, presented with cough for >2 weeks, and had a history of close contact with known DR-TB patients. These patients are considered to be “new” cases of TB with drug resistance. As both these types of patients were diagnosed specifically with drug resistance for the first time during the current illness, they were considered as “newly diagnosed” cases of DR-TB. This is important as we wanted to measure the serum lipid levels and BMI prior to starting treatment in the pretreatment initiation phase.

Of the 33 patients, 23 were males (69.7%) and 10 were females (30.3%); 45.5% of the participants were between 30 and 50 years of age, 39.4% were <30 years, and 15.2% were >50 years. Sixty-six age- and gender-matched controls were included. [Table 1] shows the baseline characteristics of the study population in comparison to that of the controls. The hemoglobin level of the test group was significantly lower compared with that of the control group.
Table 1: Baseline laboratory parameters of the drug-resistant tuberculosis patients and controls

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The DR-TB patients had serum lipid levels (all fractions) significantly lower than the controls (P < 0.001) [Table 2]. The mean BMI in the cases was 15.06 (±3.4) kg/m2 and 21.04 (±4.5) kg/m2 in the controls; the difference was statistically significant (P = 0.001). The mean radiological severity of the DR-TB patients' chest radiographs, based on the CXR score, was 51.05% (minimum 10%; maximum 90%). All the 33 cases included in the study had chest radiographs with nonhomogenous opacities of varying severity, of which, 16 had one or more cavities; however, there was no evidence of pleural effusion or lymphadenopathy in any of the films.
Table 2: Levels of serum lipid fractions in drug-resistant tuberculosis patients and controls

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Sixteen patients had a CXR score >50%, 14 had a score between 25% and 50%, and 3 patients had a score of <25%. [Table 3] shows the serum lipid levels in the DR-TB patients categorized based on the CXR score. Lower levels of TC, LDL, and VLDL were seen in those with higher radiological severity. A significant negative correlation was seen between the radiological severity and TC (r = −0.546, P = 0.001), HDL-C (r = −0.479, P = 0.005), and LDL-C (r = −0.431, P = 0.012) [Table 3]. A significant negative correlation was also seen between the radiological severity and BMI (r = −0.352, P = 0.044). Partial correlation controlling for age, BMI, hemoglobin level, total proteins, serum albumin, and serum creatinine showed a significant inverse correlation between TC and CXR score (r = −0.439, P = 0.022). However, we found that the correlation between BMI and CXR scores was not significant upon controlling for other variables (r = 0.139, P = 0.489). Backward regression analysis of the serum lipid fractions showed that the negative correlation between the radiological severity and TC was the most significant of all the lipid fractions (adjusted R2= 0.275, P < 0.001) [Figure 1]. Backward regression analysis of all the study parameters showed that the combination of TC (P = 0.15) and hemoglobin levels (P = 0.11) was the best predictor of CXR scores (adjusted R2= 0.398).
Table 3: Levels of serum lipid fractions in drug-resistant tuberculosis patients categorized based on the radiological severity

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Figure 1: Correlation between total cholesterol levels and the radiological severity of the disease in patients with drug-resistant tuberculosis

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  Discussion Top


This study showed that the radiological severity of the disease determined using chest radiograph in DR-TB patients is significantly negatively correlated with TC, LDL-C, and HDL-C, i.e., as the serum levels of cholesterol decrease, the radiological severity increases. To the best knowledge of the authors, this is the first study showing a negative correlation between the serum lipid levels and radiological severity of the disease specifically in DR-TB patients. This finding is consistent with that seen in patients with DS-TB.[8],[9]

In the current study, the mean LDL-C level was 86.06 mg/dl compared with 125.74 mg/dl in the controls. LDL-C, which has a “bad” reputation for its pro-atherogenic role, still serves the vital function of carrying cholesterol to the cells, needed for a myriad of functions including maintenance of a good immune system.[4],[5],[6] While most of the cardiovascular treatment guidelines stress on lowering LDL-C levels for the prevention of atherosclerotic vascular disease, the role of low LDL-C levels in weakening the immune system needs further investigation.[18],[19] Membrane cholesterol has been shown to interact with MHC-II (major histocompatibility complex) protein, with low levels leading to impaired antigen-presenting cell response and impaired CD4+ T-cell expansion.[19] Antigen-presenting cells are known to play a key role in containing the M. tuberculosis infection.[20],[21] Based on our study findings, we can infer that the low cholesterol levels could have resulted in a weaker immune system, resulting in a more severe infection and increased radiological severity.

In our study, the mean BMI in males was 15.06 kg/m2 and 15.79 kg/m2 in females; these values are consistent with an earlier study done in patients with pulmonary TB in rural India.[22] The presence of low BMI in patients with pulmonary TB is well established.[23] Our study found that BMI had a significant negative correlation with the radiological severity of the disease. In patients with pulmonary TB, a low BMI (<18.5 kg/m2) has been found to be associated with increased disease severity and also a higher risk of death.[24] Low BMI has also been shown to be an independent risk factor for delayed sputum culture conversion in patients with MDR-TB.[25],[26]

Low cholesterol levels and low BMI are direct measures of poor nutrition.[12] Malnutrition is known to predispose to TB.[27],[28] Underweight(BMI < 18.5) and malnutrition have been shown to be associated with decreased levels of leptin,[28]a pleiotropic hormone released by adipose tissue. Leptin is important in cell-mediated immunity as it produces lymphopoiesis and also, increases the levels of interferon-γ (IFN-γ),[28] a crucial cytokine which helps in containing the M. tuberculosis infection.[29]Therefore, decreased levels of leptin could predispose the patient to increased severity of infection by decreasing levels of IFN-γ. Low levels of leptin have been documented in patients with active TB.[30],[31] Furthermore, another hypothesis is that tubercular infection produces a chronic inflammatory reaction (with release of cytokines such as tumor necrosis factor-α and interleukin-6) in susceptible individuals, thereby decreasing leptin levels, which in turn leads to decreased cell-mediated immunity.[31]

The interplay between malnutrition and TB is complex, with malnutrition leading to TB and TB itself causing further cachexia.[27] A small randomized trial in 100 patients with TB showed that nutritional supplementation was associated with significant improvements in sputum conversion, cure rates, treatment completion rates, and performance status.[32] A cholesterol-rich diet has been shown to accelerate sputum culture sterilization rate in drug-sensitive pulmonary TB.[33] The role of nutrition as an important factor in both prevention and control of TB needs to be acted upon with more emphasis.[34] Considering TB patients as a vulnerable group for “Targeted Public Distribution System” and providing extra rations for the duration of treatment has been proposed earlier.[34] Measuring serum lipid levels prior to treatment initiation and rigorous follow-up of patients with low lipid levels could be advocated. Direct provision of nutritional supplements under the PMDT guidelines may also be considered.

Our study has limitations. It was a single-center study with a small sample size. The grading of severity on chest radiography has drawbacks due to the inherent difficulty in differentiating a pneumonic consolidation from fibrosis. Although in this study the CXR score has been considered to correlate with the overall disease severity, this may not always be true.[35]


  Conclusions Top


Our study showed that serum cholesterol levels and BMI are predictive of the radiological severity of the disease in DR-TB patients and thereby the infectivity of the patients. Prevention of transmission of disease is absolutely necessary if we intend to achieve the WHO End TB Strategy (2015) target of decreasing the incidence rates of TB by 50% by 2025.[36] In addition to medications, nutritional supplementation of the diet to increase BMI and serum cholesterol levels in patients diagnosed with DR-TB seems to be a necessary measure required to curb infectivity, and therefore, decrease the spread and incidence of the disease. More work needs to be done to confirm and re-emphasize the findings of our study.

Acknowledgment

We would like to thank Dr. Rajeshwari Devi H.R., District Medical Officer, and Dr. Badarudeen M.N., District Tuberculosis Officer, for granting the necessary clearances for conducting this study. We would also like to thank Dr. Sucharitha Suresh for her help in the statistical analysis.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.



 
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