Intensive Case Finding of Tuberculosis and Diabetes Mellitus-Bidirectional Screening of Patients Attending a Tertiary Teaching Hospital in Rural Telangana, India
Correspondence Address :
Dr. Raghuram Prasad,
Assistant Professor, Department of General Surgery, Mallareddy Medical College for Women, Suraram, Telangana-500055, Hyderabad, India.
E-mail: hod.rajive_microb@mims.edu.in
Introduction: Tuberculosis (TB) is a communicable disease of global public health threat. Poor and vulnerable populations are mainly affected with it. In association with Diabetes Mellitus (DM), TB may get worsen as increased relapse rates, delayed sputum culture conversion, increase in the case fatality rates etc. Conversely, TB may increase the incidence of DM, and worsen glycaemic control in diabetes patients.
Aim: To study the effectiveness of bidirectional screening for TB and DM in rural hospital.
Materials and Methods: A cross-sectional cohort study conducted at Medicine and Pulmonology department of MediCiti Institute of Medical Sciences (MIMS) for a period of nine months in June 2019-February 2020. All TB patients were screened for DM and vice versa. All TB patients were followed-up for treatment outcome of TB and all DM patients were followed-up for glycaemic control. Relative risk was calculated using incidence of outcome or control of disease in TB with DM patients to TB patients and DM with TB patients to DM patients.
Results: Of 256 TB patients, 38 (14.8%) were TB with DM cases. All 256 patients were followed-up for TB treatment outcome, 100% TB patients without DM had recovery, whereas 97.3% TB patients with DM had recovery after two months of therapy. Relative risk of DM on TB outcome was 0.97. Of 256 DM patients screened, 9 (3.5%) had been newly diagnosed with TB. All 256 people were followed-up for impact on glycaemic control. Relative risk of TB on glycemic control was 1.87.
Conclusion: Bidirectional screening would potentially improve care and prevention of TB and DM.`
Glycaemic control, Pulmonary tuberculosis, Relative risk, Treatment outcome
The TB is the major infectious disease among five infectious killers globally. TB is a communicable disease which remains as a global public health threat, mainly affecting population in developing countries. Every year, more than 9 million people become sick with this infectious disease, and approximately 2 million die because of it. TB in India contributes to one-fourth of the global burden. The prevalence of TB in India is 24 lakh cases (1). Telangana notification rate is 192 per one lakh population. Access to TB diagnosis and treatment is a major concern in people with TB residing in rural areas as it may get delayed (2). Hence it is essential to understand the epidemiology for appropriate interventions. In recent decades, with the increasing prevalence of DM cases in the world along with TB, the association is re-emerging as a public health priority (3). The connection of DM and TB is more significant in developing countries where TB is indigenous and the prevalence of DM is on rise (4).
National Tuberculosis Elimination Programme (NTEP) in India has also taken steps towards prevention of TB through the 3Is project. TB co-morbidities, especially Human Immunodeficiency Virus (HIV), Diabetes and Tobacco have been prioritised (5). These risk groups are to be considered for screening TB. Guidelines are already existing for detecting TB in people living with HIV (PLHIV) and for screening their contacts and in people with DM (6).
The primary objective of TB screening is to ensure early detection of TB and to initiate treatment promptly, with an eventual aim of reducing the incidence of improper treatment outcomes and other adverse ill-effects of TB, as well as helping to decrease the TB transmission. Hospital outpatient and inpatient departments and primary healthcare centres are the preferred sites and groups for screening TB as described by the NTEP. DM, a chronic metabolic disease is growing in number globally, particularly in places where burden of TB is also high. In association with DM, TB may get worsen as increased relapse rates, delayed sputum culture conversion, increase in the case fatality rates etc. even on completion of treatment (7). With the increase in the number of people with diabetes, care and control of TB may be compromised; chiefly in areas with high burden of these diseases (8). The risk increases on delay in the diagnosis. Systematic screening can be advantageous for both the groups.
Theoretically, DM and TB may complicate each other at many levels. TB infection may advance fast in people with dual burden than without (7). Conceivably, people with DM will be more prone to TB than non diabetic people leading to an increased risk of latent TB infection, but there is a feeble evidence. The clinical picture of TB in people with diabetes may change and latest diagnostic algorithms may be needed. Diabetes may quicken the appearance of drug-resistant TB, especially multidrug resistant TB (strains of TB resistant to two first line drugs, rifampicin and isoniazid) among those receiving TB treatment, although the proof is narrow (9). Reciprocally, TB may increase the incidence of DM, and exacerbate improper glycaemic control in diabetes patients (10). Moreover, TB drugs may have drug interactions with the treatment of diabetes, and diabetes may impede with the action of certain antiTB medication.
The interaction between TB and DM should be well documented. So, the World Health Organisation (WHO) and the International Union against Tuberculosis and Lung Disease (The Union) in 2011 developed a collective structure for treatment and control of TB and DM that proposed countries to take up few endeavours, such as bidirectional screening for TB and DM (11). Though this is one of the recommendations of NTEP there is limited evidence on implementation and the outcomes of bidirectional referrals (12). Studies on diabetes in TB patients in India are very limited and have used different techniques and criteria (13). This study also aligns to the recommendation from the NTEP, to screen for prevalence of TB in people with DM in medium and high-TB burden places with an average TB prevalence exceeding 100/100,000 population.
With many benefits of early detection and intensive case finding, the present study was aimed for intensive case finding of TB and DM by bidirectional screening and also to identify the effect of TB and DM on their outcome and control in the present study.
A cross-sectional screening and prospective cohort study was conducted at Medicine, Chest and TB outpatient departments of MIMS for a period of nine months in June 2019-February 2020. Subjects were recruited from patients visiting MIMS located in Medchal mandal one of the rural parts of Medchal Malkajgiri District in Telangana State, India. This hospital serves all patients with communicable and non communicable diseases. This is the teaching hospital with about 700 bedded inpatient facilities. The present study was approved by Ethical committee of MIMS. Ethical committee approval number was EC/16/IV/2k17/(1/27).
Sample size calculation: Prevalence of DM and TB co-morbidities is considered at 20% as the prevalence of DM in TB population ranged from 1.9-45% with a precision of 0.05 and Z score of 1.96 (14),(15). A probability of 5% (alpha), at which results were considered statistically significant, 95% power was applied. The sample size derived for both the groups based on the above measures was 256 each from Medicine, and chest and TB department, respectively. 10% were also added to the sample size for follow-up study. A total of 564 patients were screened and 512 patients were included in the study.
Inclusion criteria: All newly registered TB patients and all newly diagnosed or previously known DM patients with no previous history of TB of age >18 years attending the outpatient department were included after taking informed consent.
Exclusion criteria: In the DM patients group, known TB patients were excluded to avoid duplication. Patients who were lost to follow-up were also excluded from the study.
A total of 256 DM patients from Medicine department and 256 TB patients from TB and chest department of age >18yrs were studied and followed-up by the end of the study after exclusion and lost to follow-up. A total of 52 patients were excluded.
Various objectives of the study, methodology used, benefits and probable risks of present study were explained to the participants. As the study was done in rural population, research assistant had taken adequate care to ensure confidentiality as each participant had been given unique identification numbers without using names and was questioned individually (in their local language) in the examination area of the outpatient unit to ensure privacy and obtained written informed consent. The investigators and research staff signed a copy of confidentiality agreement form before study initiation. Administrative approval from the State TB Cell, Telangana was obtained for conducting the study.
Study Procedure
Potential participants for the study were identified by the physicians in the Medicine, Chest and TB outpatient departments. Data collection was done using a close-ended questionnaire given to the patients. The questionnaire has variables pertaining to age, 17social (based on kuppuswamy scale-education, income and occupation) and demographic information, symptoms for DM and TB, medication used, diagnosis of TB/DM, treatment outcomes. The questionnaire was done in Telugu or English, according to the convenience of the participant, by a research assistant who was trained and expert in the respective languages. The questionnaire was pretested by conducting a pilot testing with 20 patients and necessary changes were made and the questionnaire was validated by ethical committee. All registered TB cases were screened for DM both with symptoms and blood glucose screening. A higher Random Blood Sugar (RBS) (>200 mg/dL)/Fasting Blood Sugar (FBS) (126 mg/dL) prompted the investigator for Haemoglobin A1c (HbA1c) screening, value of more than 6.5% was diagnosed as DM (16).
HbA1c test: Glycohaemoglobin is a haemoglobin-glucose complex to which glucose gets bound to haemoglobin. Procedure was initiated by collecting whole blood samples in vacutainer tubes containing EDTA and mixed thoroughly. The minimum volume (1 mL) required for analysis was taken directly from this collection tubes and loaded into the Glycohaemoglobin analyser. Results were given as % HbA1c (17).
All registered diabetic patients from Medicine department intensive case finding of TB was done. Intensified Case Finding (ICF) is a screening activity used for earlier detection of probable TB patients in a given population. Patients with any of the four symptoms (4s positive) suggestive of TB were subjected for Sputum examination and/or chest X ray or CBNAAT (if extra pulmonary TB suspected) for TB diagnosis.
Case finding procedures
• 4s symptoms suggestive of TB: 4 symptom screening-cough >2 weeks, prolonged fever, loss of weight, loss of appetite (18).
Chest X-ray posteroanterior view: Pneumonic consolidation±
• lymphadenopathy. Miliary TB (Classic miliary TB is defined as millet like (1-5 mm) seeding of TB bacilli appearing on chest radiography (19)) or pleural effusion or pulmonary oedema are other radiological findings of TB.
• Cartridge Based Nucleic Acid Amplification Test (CB-NAAT) is a molecular method of detection of genes for Mycobacterium and also rifampicin resistance within two hours. The test was performed as per instructions [CEPHEID, Sunnyvale, CA, USA]. The procedure was done by adding sampling reagent (containing NAOH and isopropanol) and the sample in the ratio of 2:1 and incubated at room temperature for 15 minutes with shaking intermittently. Into each cartridge, 3 mL of this treated sample was taken and inserted in the module of CBNAAT machine. After an automatic process for 1hr and 50 min, results were displayed on the monitor (20).
Once sputum or X-ray or CBNAAT or clinically diagnosed as positive for TB, the patients were sent to Directly Observed Treatment Short course (DOTS) centre, where treatment and further follow-up was done.
Both the groups were followed-up by the Research assistants after the intensive phase of TB treatment and after two months of antidiabetic therapy by contact over phone or home visit. The level of glycaemic control was compared between cohort of DM patients with TB and cohort of DM patients without TB by testing HbA1c levels in blood. Sputum smear conversion after intensive phase was compared between cohort of TB patients having DM and cohort of TB patients not having DM.
Statistical Analysis
Statistical analysis was done using Statistical Package for the Social Sciences (SPSS) version 16.0. Categorical variables were depicted as counts (proportions) and Chi-square test was used for comparing categorical variables. A p<0.05 was considered statistically significant. Relative risk was calculated using incidence of outcome or control of disease in TB with DM patients to TB patients and DM with TB patients to DM patients, respectively.
A total of 512 patients, 256 TB and 256 DM patients, respectively were studied for characteristics after excluding 52 patients. Among them Male TB patients were 152 (59.4%), higher in number when compared to female TB patients who were 104 (40.6%). DM prevalence in TB was slightly higher among males 25 (16.4%) than females 13 (12.5%). Similarly, Male DM patients, 147 (57.4%) were higher in number than female DM patients, 109 (42.6%). Prevalence of TB was also high in males 9 (6.1%) compared to females 0 in DM group.
Characteristic features of TB patients and DM patients like age, sex, social and demographic factors, symptoms (DM symptoms in TB and TB symptoms in DM) and medication were compared with the characteristics of TB with DM and DM with TB patients, respectively as shown in (Table/Fig 1). Significant p-value (<0.05%) was noticed in variables such as age and symptoms.
Clinical categorisation of TB patients and DM prevalence in them are shown in (Table/Fig 2). Higher DM prevalence is shown in pulmonary TB 32 (84.2%) than in extrapulmonary TB patients 5 (13.2%) and military TB patients 1 (2.6%).
Screening for DM in TB patients: The results of screening of DM in TB patients are summarised in (Table/Fig 3). A total of 256 TB patients registered under the study were screened for DM by RBS. Among them 37 (14.4%) people had RBS >200 mg/dL. Of the 256 patients, 27 (10.5%) were known DM patients and 229 (89.5%) patients had unknown diabetic status. Among the 27 (10.5%) known DM patients, 14 (51.9%) patients had RBS >200mg/dL, in them 12 (44.4%) had HbA1C>6.5. In the remaining 229 (89.5%) patients, 13 (5.7%) had RBS>200mg/dL, among them 11 (4.8%) had HbA1C>6.5%. Therefore, 11 newly identified and the 27 (10.5%) known DM cases, a total of 38 (14.8%) TB with DM patients was sent to the medicine OPD for DM care. All 256 TB cases were followed-up after two months of initiation of ATT drugs.
Intensive case finding of TB in DM patients: A total of 256 DM patients, have been screened for symptoms of TB and also sent for X-ray, of which 42 (16.4%) patients were diagnosed as presumptive TB basing on symptoms and in them 28 (10.9%) showed X-ray findings of TB. All 42 (16.4%) presumptive TB patients were sent to the TB clinic for further diagnosis and treatment. Among them 7 (16.7%) were smear positive and 2 (4.8%) were diagnosed with extrapulmonary TB. The results of screening for TB in DM patients are summarised in (Table/Fig 4).
The 9 (3.5%) DM patients confirmed with TB were started on ATT drugs.
Treatment outcomes of TB patients on follow-up: The results of the 512 patients came follow-up for treatment outcome in TB patients and glycaemic control in the DM patients separately are summarised in (Table/Fig 5). A total of 256 TB patients came for follow-up, among them only one patient had not recovered from TB (had smear positive after the intensive phase). The patient was a known Diabetic and had improper glycaemic control. So, 218 (100%) of 218 TB patients without DM had recovery, whereas 37 (97.3%) of the 38 TB patients with DM were recovering after two months of ATT therapy. Relative risk of DM on TB outcome was 0.97.
Follow-up of DM patients for glycaemic control and impact of TB: 256 DM patients came for follow-up after two months, the glycaemic control was tested by means of HbA1C. The results of glycaemic control and impact of TB are summarised in (Table/Fig 5). Of the 256 DM patients tested for HbA1C after two months, 115 (48%) had HbA1C >6.5%. Of them, 8 (7%) were DM with TB patients. Of the 9 (3.5%) DM patients with TB, 8 (88.8%) had impaired glycaemic control which was more compared to 107 (46.6%) showed improper glycaemic control among 247 (96.5%) DM without TB patients. Relative risk of TB on glycaemic control was 1.87. Tuberculosis showed significant effect on glycaemic control in DM with TB patients.
The finding of the study provides valuable insights into TB-DM prevalence and the impact of each other on treatment outcome. First, bidirectional screening was implemented for TB and DM. All TB patients were screened for DM and vice versa. The reason why all participants registered could be screened was close proximity of TB clinics and Medicine department in a tertiary care centre. But, when follow-up was done to know the impact on treatment outcome of TB and DM, there were drop outs because of the loss or change in contact number of the patients. To overcome this 10% more patients were screened so that number of patients studied and follow-up remains the same in both the groups.
About 14.8% TB patients registered for the study had DM. Nearly 2/3rd of all identified DM patients were known diabetic. According to literature, the DM prevalence in TB patients varies from a maximum of 29% in Puducherry to a minimum of 6.1% in Kashmir valley (21),(22). A large metacentric study found 13% prevalence of DM among TB across India (23). The present study was in correlation with other studies, but showing slightly less prevalence than studies conducted at other places of South India where it is from 12.1% in Bangalore to 29% in Puducherry (24),(26),(27). As this study was conducted in a rural area, there were less number of cases reported; this may be due to more physical activity in people living in rural area compared to the people in urban areas. However prevalence has regional variations, which may also be one reason (26).
In TB patients screened, higher median age patients noted who had diabetes, similar findings in Prakash BC et al., study which showed high TB with DM were seen in >40 years and study by Menon VU et al., identified that the prevalence of diabetes by age showed an increase in number after age of 50 (24),(25). Present study showed association with hyperglycaemia was higher with pulmonary TB showed similarity to other studies (27). In a case-control study in the United States, patients having pulmonary TB had a higher prevalence of DM than the patients having extrapulmonary TB (28).
There are various mechanisms described by which TB can initiate DM. The pressure caused by TB on the body leads to increased hormonal level such as increase in cortisol which in turn increase blood sugars; and also due to let out of different cytokines, chemokines and tubercular proteins may lead to dysfunction of pancreas. This may be due to the deposition of amylin within the pancreas or may be due to entry by the Mycobacteria into pancreas (29),(30).
In present study, nearly 16.4% of DM patients screened had symptoms suggestive of TB. This was higher than in general population, as it was evaluated as 2-3% of patients had TB symptoms (31),(32). Present study found only few TB cases (3.5%), may be due to adequate glycaemic control in patients attending tertiary care centre there could be a low risk of TB in them (33). Other reason for the low detection rate may be due to nonperformance of CBNAAT or Acid Fast Bacilli (AFB) culture for smear negative cases. Inspite of this, these results are correlating with other studies done in DM clinics all over India (34).
Infections are common when there is impaired glucose tolerance, TB is common among them.
The relative risk of DM on TB treatment outcome of TB patients was noted in the study as 0.97. This can be due to absence of unrecovered patients in the control group (TB without DM). Nine studies assessed the effect of DM on prolonged positivity of TB bacilli at 2-3 months of treatment, among them six study groups in different studies have expressed relative risks (RRs) of >2 (35),(36),(37),(38) and three studies stated RRs of <1 (7),(36),(39). Relative risks of improper recovery of TB was ranging from 2.95 in Hispanics, 1.31 in non Hispanic Whites, and 0.93 in non Hispanic Black patients (36).
The impact of TB on glycaemic control is clearly noticed in the present study as 88.8% of DM patients had impaired glycaemic control where as 46.6% of DM patients without TB had impaired glycaemic control. This results correlates with the study by Krishnappa D et al., (27). Relative risk noted as 1.87 in present study. The treatment of the DM is affected may be because of the hampering of drug efficacy or increased survival of the Mycobacteria or due to antitubercular drugs used for TB (40).
Limitation(s)
Long-term studies with bigger sample size are needed to determine the relationship of these chronic diseases in detail.
The present study reports that DM and TB have bidirectional relationship. Considering the increasing burden of DM, particularly in areas with highly prevalent TB, these studies will be helpful for intensive case finding. Interdepartmental collaborative activities would also potentially improve care and prevention.
DOI: 10.7860/JCDR/2022/55850.16712
Date of Submission: Feb 22, 2022
Date of Peer Review: Apr 13, 2022
Date of Acceptance: May 17, 2022
Date of Publishing: Aug 01, 2022
AUTHOR DECLARATION:
• Financial or Other Competing Interests: NTEP authority for providing support with OR research grant (2016).
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA
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