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Raised levels of IFN-gamma and IL-13 are associated with pre-diabetes amongst newly diagnosed patients with Tuberculosis.

Byline: Zahra Hasan, Muhammad Irfan, Qamar Masood, Owais Ahmed, Umme Salama Moosajee, Shoaib Rao and Naseem Salahuddin

Keywords: Pre-diabetes, Tuberculosis, Interleukin-13, Diabetes, Interferon-gamma.

Introduction

Tuberculosis (TB) results in approximately 1.7 million deaths each year.1 Pakistan ranks 5th amongst high TB-burden countries worldwide, with an incidence of 268/100,000 annually.1 Pakistan has a diabetes prevalence of 6.9%, ranks 7th amongst high diabetes-burden countries and there are estimated to be 3.5 million undiagnosed diabetics in the country.2 In TB with diabetes, there is an increased risk of death due to TB treatment and of TB relapse after treatment.3 The World Health Organisation (WHO) recommends bidirectional screening of TB in patients with diabetes, and for diabetes in TB patients.4 Unfortunately, both TB and diabetes are often not detected early and their public health burden is high.

Mycobacterium tuberculosis (Mtb), the causative agent of TB, resides within macrophages and can be restricted by the appropriate activation of T cells and macrophages regulated by cytokines such as interferon-gamma (IFN), tumour necrosis factor alpha (TNF), interleukin (IL)-2 and IL-10. Impaired T cell mediated immune responses have been demonstrated in Mtb infected individuals with type 2 diabetes mellitus (T2DM). 5 Bacterial loads in macrophages from diabetic individuals with TB have been shown to be higher than in non-diabetics.6 The mechanism responsible for immune deficiency in diabetes that leads to exacerbation of TB is as yet unclear. TB remains common but many patients remain unaware of having diabetes. Overall, the data regarding rates of diabetes amongst TB patients in Pakistan ranges 11-30%.7,8 Cytokines are shown to be immune markers for TB disease severity and outcome.9

Raised levels of pro-inflammatory IFN, TNF and IL-10 have been associated with advanced TB.10,11 In diabetes, T cell IFN responses are found to be defective.12 In TB patients with DM and pre-DM, it has been shown that pro-inflammatory cytokines are raised, indicating heightened responsiveness to stimuli.13,14 There is as yet limited understanding of the immune mechanisms responsible for poorer immune responses to Mtb in DM patients and also the identification of potential biomarkers of DM and TB. The current study was planned to screen newly-diagnosed TB patients for random blood glucose (RBG) and glycosylated haemoglobin (HbA1c) levels. Further, we determined serum levels of type 1 T helper (Th1) and Th2 cytokine levels in the patients to investigate the association between blood glucose levels and TB.

Patients and Methods

The cross-sectional study was conducted from May to November 2015 at Indus Hospital and The Aga Khan University Hospital (AKUH), Karachi after approval was obtained from the ethical review committees of Aga Khan University Hospital (AKUH), Karachi, and Indus Hospital, Karachi. Written informed consent was taken from each subject. The sample size was calculated based on the prevalence of diabetes identified in Pakistan in 2015, 6.8%.2 In TB patients there is a 2-3 time risk of diabetes,15 thus the prevalence rate was estimated at 13-20%. The estimate of the expected proportion (p) rate was set at 13-20% by taking average proportion i.e. 16.5% with 5% desired level of absolute precision (d) for 95% confidence interval (CI) with 5% level of significance. Those included were subjects from either gender aged 18 years or more with a confirmed TB diagnosis and who were either newly-diagnosed or had received up to 1 month of anti-tuberculous therapy (ATT).

Those aged less than 18 years, and patients who had received more than one month of ATT were excluded. Using consecutive sampling method, patients were enrolled from among those presenting to the TB clinics at the two hospitals. Diagnosis of TB was made according to the National TB Programme guidelines16 on the basis of characteristic clinical features; chest X-rays/a positive sputum smear and or/Xpert TB/RIF assay (Cepheid, USA). Sputum, when available for testing, was sent for both acid fast bacillus (AFB) smear microscopy and Xpert testing. In cases where sputum was not produced, patients were identified as pulmonary TB (PTB) cases based on strong radiological findings and clinical correlation. Diagnosis of extrapulmonary TB (EPTB) was made on a positive Xpert test of site-specific specimen or histopathology confirming granulomatous inflammation, and co-incident with clinical history.

Patients with EPTB had either pleural TB, tuberculous lymphadenopathy (LNTB), abdominal TB or other extrapulmonary site involvement. Detailed demographic information and information regarding clinical algorithm was logged by an attending medical officer on a pre-designed proforma. Blood samples from each subject were screened for diabetes by testing for RBG and HbA1c. Body mass index (BMI) was calculated for each patient based on their weight and height measurements at baseline. The categories were set at less than 18*5 kg/m2 underweight; 18*5-22.9 kg/m2 normal weight; 23-27*4 kg/m2 overweight; and 27*5 kg/m2 obese. 17 Normal levels of HbA1c were less than 39 mmol/mol (5.7%). Diabetes was defined by HbA1c [greater than or equal to] 48 mmol/mol (6.5%), and pre-diabetes at HbA1c 39-44 mmol/mol (5.7-6.4%).18 Serum samples from study subjects were tested using the Bio-Plex Pro Human Cytokine (27-Plex Panel, Bio-Rad, USA) as per the manufacturer's instructions.

The cytokines detected were IFNI3, IL-10, IL-12p70, IL-13, IL-2, IL-5, IP-10, MiP-1[alpha], MiP-1[beta], IL-6, IL1-RA, GM-CSF, RANTES, IL-1[beta], Eotaxin, Basic FGF, VEGF, PDGF-[beta], MCP-1, IL-8, IL15, IL-17, G-CSF, IL-12p70, IL17A, IL-9 and TNF-[alpha]. Tests were performed on the Luminex 200 system (MERCK laboratories, USA). Data analysis was done using SPSS version 19.0. Mann-Whitney U test was used to compare non-parametric variables. Significance of 95% CI was used to determine significant difference between variables which was set at pa$?0.05.

Table-1: Description of study sample.

###Total n(%)

Age(years)(n=211)###a$?25###100(47.4)

###26-50###76(36.0)

###>50###35(16.6)

Gender(n=211)###Male###101(47.9)

###Female###110(52.1)

BMI kg/m2 with Categories(n=167)###Underweight(<18.5)###100(47.3)

###Normal(18.5-22.9)###44(20.9)

###Overweight(23-27.4)###11(5.7)

###Obese([greater than or equal to]27.5)###12(5.7)

Site of TB###Pulmonary TB###172(81.5)

###Extra Pulmonary TB###39(18.5)

Category of Treatment(n=211)###New treatment###165(78.2)

###Retreatment###46(21.8)

Family History of TB(n=211)###Positive Family History###76(36.0)

###No Family History###135(64.0)

Table-2: Microbiological and Radiological description of TB cases (n=211).

###n(% of total)###Result###n(%)

PTB cases###172(81.5%)

Sputum AFB Smear###150(87%)###Positive###70(46.7)

###Negative###80(53.3)

Sputum Xpert MTB/RIF###144(84%)###Positive###121(84)

###Negative###23(16)

###Indeterminate###2(1.7)

Xpert MTB/RIF Result###121(57.3%)###Not Detected###118(97.5)

###Detected###1(0.8)

Chest X-Ray###157(74.4%)###Minimal###18(11.5)

###Moderate###85(54.1)

###Advanced###54(34.4)

EPTB cases###39(18.5%)

Category of TB###Pleural###16(41)

###Abdominal###9(23)

###Lymph node###7(17.9)

###Bone and joint###2(5.1)

###Others###5(12.8)

Table-3: Characteristics of study subjects as per diabetes status (n=211).

###Total###Median###HbA1c IQR=Median(Q3 -Q1)###RBG

###n(%)###Age(Years)###IFCC(mmol/mol) NGSP HbA1c %###IQR=Median(Q3 -Q1)

Non-Diabetics###142(67.30%)###23###34 mmol/mol(37-31) 5.30%(5.50-5.00)###95(108-89)

Pre-Diabetics###45(21.30%)###40###40 mmol/mol(42-39) 5.80%(6.00-5.70)###100(122-93)

Diabetics###24(11.40%)###50###92 mmol/mol(108-81) 10.6%(12.00-9.55)###281(390-191)

Total###211(100%)###26###37 mmol/mol(40-32) 5.50%(5.80-5.10)###98(118-90)

p-value###----###p<0.0001*###p<0.0001*###p<0.0001*

Table-4: Comparison of TB patients as per glycaemic levels.

###Total n(%)###Non-Diabetics n(%)###Pre-Diabetics n(%)###Diabetics n(%)

Gender###Male###101(47.9)###58(57.4)###29(28.7)###14(13.9)

###Female###110(52.1)###84(76.4)###16(15.5)###10(9.1)

BMI(kg/m2) with Categories(n=167)###Underweight(<18.5(kg/m2))###100(60)###77(77)###18(18)###5(5)

###Normal(18.5-22.9)###44(26.3)###30(68.2)###7(16.2)###7(16.2)

###Overweight(23-27.4)###11(6.6)###4(36.4)###4(36.4)###3(27.3)

###Obese(27.5)###12(7.2)###4(33.3)###6(50)###2(16.7)

Site of TB###Pulmonary TB###172(81.5)###109(63.4)###39(22.7)###24(14)

###Extra Pulmonary TB###39(28.5)###33(84.6)###6(15.4)###0

Category of Treatment###New treatment###165(78.2)###108(65.5)###36(21.8)###21(12.7)

###Retreatment###46(21.8)###34(73.9)###9(19.6)###3(6.5)

Table-5: Circulating cytokine values.

###n###IFN I3###IL-10###IL-12p70###IL-13###IL-2###IL-5###TNF-

###Mean+-SD(pg/ml)###Mean+-SD(pg/ml)###Mean+-SD(pg/ml)###Mean+-SD(pg/ml)###Mean+-SD(pg/ml)###Mean+-SD(pg/ml)###Mean+-SD(pg/ml)

Normal###38###27.58 +-89.65###155.56 +- 490.18###117.66 +- 437.49###2.90+-17.85###0.00###25.24 +-155.60###112.07+-416.08

Pre-diabetic###24###444.11 +-1298.58###261.47 +- 747.79###362.00 +- 835.35###72.23 +-210.24###63.20 +- 220.39###102.63 +-263.72###730.74+-2448.77

Diabetic###13###257.30 +-746.37###0.00###128.16 +- 462.07###68.00 +-245.19###64.34 +-231.98###76.84 +- 277.05###1700.78+-5881.97

p-value###0.028*###NS###NS###0.003*###NS###NS###NS

Results

Of the 216 patients initially approached, 4(1.8%) refused to give a blood sample while 1(0.45%) was lost due to haemolysis. After data collection 1(0.45%) patient had to be excluded due to old age which was identified later. The final sample, as such, stood at 211(97%). Of them, 110(52%) were females and 101(48%) were males. The overall median age of the sample was 26 years, and 1 00(47.3%) subjects were under weight (Table 1). The BMI values were available for 167(79%) subjects and, among them, median BMI was 17.78 kg/m2. The median number of members in each household was 7, and 76(36%) cases had a family history/household contact with TB patients. Overall, 165(78.2%) cases were new and 46 (21.8%) were re-treatment cases. At the time of recruitment, 135(63.5%) were newly-diagnosed and had not received ATT while 76 (36.5%) cases had received one month of ATT.

In terms of co-morbid conditions, 2(0.9%) patients had human immunodeficiency virus (HIV) infection, 3(1.3%) subjects had viral hepatitis B or C, 3(1.3%) were intravenous drug users (IDUs) and 1(0.45%) had an autoimmune disease. Besides, 7(3.3%) subjects were known diabetics and were on treatment for hyperglycaemia. Further, there were 172(81%) cases of PTB and 39(19%) of EPTB (Table 2). Sputum was available for testing in 150 (87%) cases. Where sputum was not produced, patients were identified as PTB cases based on strong radiological findings and clinical correlation. On sputum testing, 70(46.7%) had a positive AFB smear. Of the 144(68%) cases in which sputum Xpert test was peformed, 121(84%) had a positive result; 118 (97.5%) had rifampicin-susceptible Mtb, 1 (0.8%) had rifampicin-resistant Mtb, and 2(1.6%) had indeterminate results.

Overall, 70 (41%) of 172 PTB patients were diagnosed on the basis of AFB smear being positive, and 121 (70%) were diagnosed via positive Xpert TB result. Of the PTB cases, 85(54.1%) had moderate disease on chest radiograph followed by advanced disease 54(34.4%) and minimal disease in 18 (11.5%). Of the 39 EPTB cases, 32(82%) had a normal chest X-ray. The EPTB cases comprised pleural 16(41%), abdominal 9(23%), lymph-node TB 7(18%), bone and joint 2 (5%), and the remaining 5(13%) cases had additional sites involved. Based on HbA1c and RBG test results, 142 (67.3%) patients had normal glycaemic levels, 45(21.3%) were pre-diabetics and 24(11.4%) were diabetics (Table 3). The median HbA1c levels of normoglycaemics was 5.3%, pre-diabetics 5.8% and diabetics 10.6%. Median RBG levels were 95 g/dl for normal, 100 g/dl for pre-diabetics and 281 g/dl for diabetics. TB patients with diabetes were comparatively older than the rest (p<0.001).

Of the diabetic patients, 17(71%) were newly-diagnosed while 7(29%) already knew they had diabetes. Among the diabetics, 14(58%) were males and 10(42%) were females (Table 4). Among the pre - diabetics, 29(28.7%) were males compared to 16(15.5%) women ((p=0.026). Among the 100(47.3%) underweight individuals, 77(77%) were non-diabetics, 18(18%) pre-diabetics and 5(5%) were diabetics. Amongst TB patients with normal weight, the corresponding values were 30(68%), 7(16%) and 7(16%). Among the overweight TB patients, the values were 4(36.4%) non-diabetics, 4(36.4%) pre-diabetics and 3(27%) diabetics. In the obese TB cases, there were 4(33.3%) non-diabetics, 6(50%) pre-diabetics and 2(16.7%) diabetics. Circulating serum levels of cytokines were measured in 75 (35.5%). Of them, 13 (17.3%) had diabetes, 24 (32%) had pre-diabetes, and 38(51%) were non-diabetics. Significantly different levels of IFNI3 (p=0.028) and IL-13 (p=0.003) were obser ved among normoglycaemic, diabetic and pre-diabetic cases.

IFNI3 levels in individuals with pre-DM were greater than those with DM (p=0.028) and normoglycaemic (p=0.007) TB patients. Also, IL-13 was raised in pre-DM compared to DM (p=0.003) and normoglycaemics (p=0.001). Levels of IL-10, IL-12p70, IL-2 and IL-5 were comparable between normoglycaemic, diabetic and non-diabetic TB patients (Table 5). HbA1c levels showed a weak but significant correlation with IFNI3 (p=0.23, rho=0.262).

Discussion

This, to our knowledge, is the first study to identify rates of pre-DM in a cohort of newly-diagnosed TB patients in Pakistan. Also, it identified IFNI3 and IL-13 as biomarkers of individuals with TB and pre-DM. Pre-diabetes is a state which can often be managed with exercise and healthy eating. Identification of diabetes or pre-diabetes, defined also as intermediate diabetes, is important as uncontrolled blood glucose levels result in unfavourable outcomes in TB patients.19 A study in Karachi recently showed that diabetics were 10 times more likely to have TB than non-diabetics.20 Previous studies have reported rates of diabetes amongst TB patients as 11-30% (7, 8). This has further varied to 6% of newly-diagnosed diabetics amongst TB patients21 while another revealed that there were 39%8 diabetics amongst TB patients. The current study identified 11.4% cases of diabetes and 21.3% cases of pre-diabetes.

The percentage of diabetics found here and in previous studies is higher than the prevalence of 6.9% shown nationwide.2 These variations could be due to the cohort tested and also due to differences in methods used to assess diabetes, as there may be differences due to cut-offs by fasting blood glucose (FBG), HbA1c and oral glucose tolerance test (OGTT) methods. The higher proportion of TB patients with pulmonary compared with EPTB matches the trends reported globally. Most patients were under the age of 25 years, meaning TB occurs predominantly in young adults.1 The trend of high household contacts for each individual was similar to those reported previously.22 The rate of 36% amongst those with prior family history of TB suggests that the majority of TB cases were a result of new contact with TB patients. The age group of diabetics showed an older age distribution than those who didn't have diabetes, as shown previously.8

The reduced BMI in TB patients with the majority of cases being underweight fits previous reports.8 When patients were further differentiated as per BMI categories17 and were correlated with their glycaemic status, it was apparent that amongst the overweight and obese TB patients there was a larger proportion of cases who were pre-diabetic and diabetic compared to the proportion of pre-diabetic and diabetic cases found in the under weight and normal weight groups. This correlates with previous reports that showed an increased association of diabetes with raised BMI in TB patients.7 An impaired T cell mediated immune response has been demonstrated.5 Bacterial loads in macrophages from diabetic individuals with TB are higher than in non-diabetics.6 This leads to less favourable outcomes in TB patients who have diabetes. Pre-diabetes is a state which can often be managed with exercise and healthy eating. We found that 21% of newly-diagnosed TB patients were pre-diabetic.

Further, it was apparent that IFNI3 and IL-13 levels were significantly higher in those with pre-DM compared with DM and normoglycaemic TB patients. A recent study showed there was a diminished inflammatory response to Mtb in individuals who had latent TB coincident with pre-diabetes.23 Separately, certain inflammatory markers such as immunoglobulin E (IgE), IL-4, IL-10, and tryptase have been positively associated with pre-diabetes or T2DM.24 Our data indicating an increase in IFNI3 levels in pre-DM TB patients confers with previous reports.13 However, a study observed an increase in additional cytokines Type 1 and Type 2.13 Another difference from this study was that we observed a weak but significant correlation between IFNI3 levels and HbA1c levels in TB patients, which was in contrast to that observed by a previous study.13 It is of note that IL-13 was found to be raised in TB patients with pre-DM.

Our observation that IL-13 levels are reduced in DM is in line with reduced glycaemic control. IL-13 is a Th2 cytokine known to mediate macrophage alternate activation. IL-13 knockout mice have been shown to display hyperglycaemia resulting in hepatic insulin resistance and systemic metabolic dysfunction.2 5 Therefore, IL-13 is important for the regulation of glucose metabolism. During TB treatment there is a transient state of hyperglycaemia.26 This is likely to be further raised in those with previously raised blood glucose levels. Uncontrolled hyperglycaemia leads to chronic inflammation. Therefore, in the absence of a homeostatic balance of cytokines immune responses to Mtb infection will be defective.

Conclusions

IL-13 and IFNI3 were identified as biomarkers of pre-diabetes in TB patients. There is a need for early identification and management of diabetes and pre-diabetes in TB.

Disclaimer: None.

Conflict of Interest: None.

Source of Funding: The study received technical and financial support from the World Health Organisation (WHO) Special Programme for Research and Training in Tropical Diseases (TDR): The EMRO/TDR Small Grant Scheme for Operational Research in Communicable Diseases.

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