Application of mobile phone technology as intervention for the management of tuberculosis patients diagnosed through community survey.

Background & objectives: The delay in communicating the results to tuberculosis (TB) patients leads to increased rates of initial loss to follow up of treatment. The gap in communication among healthcare providers requires application of new tools that will address the challenges. Mobile phone technologies could be a useful tool in this context for the delivery of information. The objective was thus to evaluate communication by mobile applications such as the WhatsApp Messenger to decrease initial loss to follow up after initial treatment for TB. Methods: Indian Council of Medical Research-National Institute for Research in Tuberculosis, Chennai, India undertook a community prevalence survey to find the burden of TB. During this survey, mobile phone-based technology (WhatsApp messenger) was employed as an intervention among the healthcare providers and researchers involved for communicating. This was further evaluated for its usefulness by examining the initial loss to follow up and patients initiated on treatment. Results: The study covered four blocks of Thiruvallur district of Tamil Nadu, South India, namely Kadambathur, Poondi, Thiruvalangadu and Periyapalayam. The survey population was around 20,000 from each block, and the average patients diagnosed by community TB prevalence survey were 30 patients from each block. Among the patients diagnosed through this survey, in the first block, only 55 per cent were initiated on treatment; subsequently, with the intervention, the initial loss to follow up was significantly reduced from 45 to zero per cent. Interpretation & conclusions: After integrating of WhatsApp messenger application for communication among healthcare providers and researchers, the initial loss to follow up among patients being treated for TB was significantly decreased.

Seroprevalence of Strongyloides stercoralis infection in a South Indian adult population.

BACKGROUND: The prevalence of Strongyloides stercoralis infection is estimated to be 30-100 million worldwide, although this an underestimate. Most cases remain undiagnosed due to the asymptomatic nature of the infection. We wanted to estimate the seroprevalence of S. stercoralis infection in a South Indian adult population. METHODS: To this end, we performed community-based screening of 2351 individuals (aged 18-65) in Kanchipuram District of Tamil Nadu between 2013 and 2020. Serological testing for S. stercoralis was performed using the NIE ELISA. RESULTS: Our data shows a seroprevalence of 33% (768/2351) for S. stercoralis infection which had a higher prevalence among males 36% (386/1069) than among females 29.8% (382/1282). Adults aged ≥55 (aOR = 1.65, 95% CI: 1.25-2.18) showed higher adjusted odds of association compared with other age groups. Eosinophil levels (39%) (aOR = 1.43, 95% CI: 1.19-1.74) and hemoglobin levels (24%) (aOR = 1.25, 95% CI: 1.11-1.53) were significantly associated with S. stercoralis infection. In contrast, low BMI (aOR = 1.15, 95% CI: 0.82-1.61) or the presence of diabetes mellitus (OR = 1.18, 95% CI: 0.83-1.69) was not associated with S. stercoralis seropositivity. CONCLUSIONS: Our study provides evidence for a very high baseline prevalence of S. stercoralis infection in South Indian communities and this information could provide realistic and concrete planning of control measures.

Prevalence of bacteriologically confirmed pulmonary tuberculosis and associated risk factors: A community survey in Thirvallur District, south India.

BACKGROUND: Tuberculosis (TB) prevalence surveys add to the active case detection in the community level burden of TB both national and regional levels. The aim of this study was to assess the prevalence of bacteriologically confirmed pulmonary tuberculosis (PTB) in the community. METHODS: Household community-based tuberculosis disease survey was conducted targeting 69054 population from 43 villages of 5 blocks in Tiruvallure district adopting cluster sampling methodology of ≥15 years old adult rural population of South India during 2015-2018. All eligible individuals with suspected symptoms of PTB were screened with chest X-ray. Two sputum specimens (one spot and the other early morning sample) were collected for M.tb smear and culture examination. Conversely demographical, smoking and alcohol drinking habits information were also collected to explore the risk factor. Stepwise logistic regression was employed to associate risk factors for PTB. RESULTS: A total of 62494 were screened among 69054 eligible population, of whom 6340 were eligible for sputum specimen collection. Sputum for M.tb smear and culture examination were collected in 93% of participants. The derived prevalence of PTB was 307/100000 population (smear-positive 130; culture positive 277). As expected that PTB has decreased substantially compared to preceding surveys and it showed that older age, male, low BMI, diabetes, earlier history of TB and alcohol users were significantly associated (p < .0001) with an increased risk of developing PTB. CONCLUSION: Upshot of the active survey has established a reduction in the prevalence of PTB in the rural area which can be accredited to better programmatic implementation and success of the National TB Control Programme in this district. It also has highlighted the need for risk reduction interventions accelerate faster elimination of TB.

Impact of malnutrition on systemic immune and metabolic profiles in type 2 diabetes.

BACKGROUND: While obesity and overweight status are firmly established risk factors for Type 2 diabetes mellitus (T2DM), a substantial proportion of diabetic individuals, especially in Africa and Asia, are often underweight or normal weight. However, very little is known about the immunological and metabolic profiles of these individuals. METHODS: This study aimed to assess the relationship between malnutrition and Type 2 diabetes mellitus (T2DM). We examined a variety of analytes associated with the immunological and metabolic profiles of T2DM individuals with low (< 18.5 kg/m2) or normal (18.5-24.9 kg/m2) body mass index (BMI). To this end, we measured plasma levels of HbA1c, glucose, insulin, glucagon, adipocytokines and Type 1, Type 2, Type 17, pro-inflammatory and regulatory cytokines in T2DM individuals with low BMI (LBMI) or normal BMI (NBMI) with small sample size n = 44 in each group. RESULTS: LBMI individuals exhibited significantly higher levels of HbA1c, random blood glucose, insulin and glucagon compared to NBMI individuals. Similarly, LBMI individuals exhibited significantly higher levels of adiponectin and adipsin and significantly lower levels of leptin in comparison to NBMI individuals. LBMI individuals also exhibited significantly lower levels of the Type 1, Type 2, Type 17, pro-inflammatory and regulatory cytokines in comparison to NBMI individuals. Finally, while the metabolic parameters exhibited a significant negative correlation with BMI, the immunological parameters exhibited a significant positive correlation with BMI. CONCLUSIONS: Malnutrition is associated with a significant modulation of glycemic, hormonal and cytokine parameters in T2DM. Hence, the biochemical and immunological profiles of T2DM is significantly influenced by BMI.

Tuberculosis preventive treatment should be considered for all household contacts of pulmonary tuberculosis patients in India.

The World Health Organization (WHO) recently changed its guidance for tuberculosis (TB) preventive treatment (TPT) recommending TPT for all pulmonary TB (PTB) exposed household contacts (HHC) to prevent incident TB disease (iTBD), regardless of TB infection (TBI) status. However, this recommendation was conditional as the strength of evidence was not strong. We assessed risk factors for iTBD in recently-exposed adult and pediatric Indian HHC, to determine which HHC subgroups might benefit most from TPT. We prospectively enrolled consenting HHC of adult PTB patients in Pune and Chennai, India. They underwent clinical, microbiologic and radiologic screening for TB disease (TBD) and TBI, at enrollment, 4-6, 12 and 24 months. TBI testing was performed by tuberculin skin test (TST) and Quantiferon®- Gold-in-Tube (QGIT) assay. HHC without baseline TBD were followed for development of iTBI and iTBD. Using mixed-effect Poisson regression, we assessed baseline characteristics including TBI status, and incident TBI (iTBI) using several TST and/or QGIT cut-offs, as potential risk factors for iTBD. Of 1051 HHC enrolled, 42 (4%) with baseline TBD and 12 (1%) with no baseline TBI test available, were excluded. Of the remaining 997 HHC, 707 (71%) had baseline TBI (TST #x2265; 5 mm or QGIT #x2265; 0.35 IU/ml). Overall, 20 HHC (2%) developed iTBD (12 cases/1000 person-years, 95%CI: 8-19). HIV infection (aIRR = 29.08, 95% CI: 2.38-355.77, p = 0.01) and undernutrition (aIRR = 6.16, 95% CI: 1.89-20.03, p = 0.003) were independently associated with iTBD. iTBD was not associated with age, diabetes mellitus, smoking, alcohol, and baseline TBI, or iTBI, regardless of TST (#x2265; 5 mm, #x2265; 10 mm, #x2265; 6 mm increase) or QGIT (#x2265; 0.35 IU/ml, #x2265; 0.7 IU/ml) cut-offs. Given the high overall risk of iTBD among recently exposed HHCs, and the lack of association between TBI status and iTBD, our findings support the new WHO recommendation to offer TPT to all HHC of PTB patients residing in a high TB burden country such as India, and do not suggest any benefit of TBI testing at baseline or during follow-up to risk stratify recently-exposed HHC for TPT.

Diminished Systemic and Mycobacterial Antigen Specific Anti-microbial Peptide Responses in Low Body Mass Index-Latent Tuberculosis Co-morbidity.

Low body mass index (BMI) is a risk factor for progression from latent Mycobacterium tuberculosis infection to active tuberculosis (TB) disease. Anti-microbial peptides (AMPs) are multifunctional molecules that play a crucial role in the mammalian host innate defense mechanism. AMPs have been shown to have an important role in host immunity to TB infection. The association of antimicrobial peptides with low BMI-latent tuberculosis (LTBI) co-morbidity has not been explored. To study the association of AMPs with LTBI-BMI, we examined the systemic, baseline, and mycobacterial antigen stimulated levels of human neutrophil peptides 1-3, (HNP1-3), granulysin, human beta defensin-2 (HBD-2), and cathelicidin (LL-37) in individuals with LTBI and low BMI (LBMI) and compared them with individuals with LTBI and normal BMI (NBMI). LBMI was characterized by diminished systemic levels of HNP1-3, granulysin, HBD-2 and cathelicidin in comparison with NBMI. Similarly, LBMI was also characterized by diminished unstimulated levels of HNP1-3 and granulysin and diminished mycobacterial antigen stimulated levels of HNP1-3, granulysin, and HBD-2. In addition, certain AMPs exhibited a positive correlation with BMI. Our data, therefore, demonstrates that coexistent LBMI in LTBI is characterized by the diminished levels of HNP1-3, granulysin, HBD-2, and cathelicidin, thereby potentially increasing the risk of progression to active TB.

Catastrophic costs due to tuberculosis in South India: comparison between active and passive case finding.

BACKGROUND: To measure and compare economic burden at the household level for tuberculosis (TB) patients who were detected through active case finding (ACF) and passive case finding (PCF) in rural areas. METHODS: This study was conducted in the Thiruvallur district from October 2016 to March 2018. TB patients diagnosed through ACF were included in this study. For the comparison, patients diagnosed through ACF were recruited in the ratio of 1:2 from the same study area during the same period. Costs between the groups were compared and a multiple regression model was used to identify factors associated with catastrophic costs due to TB. RESULTS: Of the 336 individuals, 110 were diagnosed through ACF and 226 through PCF. A total of 29% of patients diagnosed through PCF and 9% of patients diagnosed through ACF experienced catastrophic costs due to TB. The multiple logistic model shows that catastrophic costs due to TB had a significant association with higher income status (adjusted odds ratio [aOR] 4.91 [confidence interval {CI} 2.39 to 10.08]; p<0.001), alcohol use (aOR 2.78 [CI 1.33 to 5.81]; p=0.007), private as a first point of care (aOR 3.91 [CI 2.01 to 7.60]; p<0.001) and PCF (aOR 3.68 [CI 1.62 to 8.33]; p=0.002). CONCLUSIONS: Findings highlight that ACF significantly averted catastrophic costs due to TB among patients. ACF as a strategy could ensure financial protection of TB patients and limit their risk of poverty.

Undernutrition is associated with perturbations in T cell-, B cell-, monocyte- and dendritic cell- subsets in latent Mycobacterium tuberculosis infection.

Undernutrition, as described by low body mass index (BMI), is a foremost risk factor for the progression of active Tuberculosis (TB). Undernutrition is also known to impact the baseline frequencies of innate and adaptive immune cells in animal models. To verify whether undernutrition has any influence on the baseline frequencies of immune cells in latent Mycobacterium tuberculosis infection (LTBI), we examined the frequencies of T cell-, B cell, monocyte- and dendritic cell (DC)- subsets in individuals with LTBI and low BMI (LBMI) and contrasted them with LTBI and normal BMI (NBMI) groups. LBMI was characterized by decreased frequencies and absolute cell counts of T cells, B cells and NK cells in comparison with NBMI. LBMI individuals demonstrated significantly enhanced frequencies of naïve and effector CD4+ and CD8+ T cells and significantly decreased frequencies of central memory, effector memory CD4+ and CD8+ T cells and regulatory T cells. Among B cell subsets, LBMI individuals demonstrated significantly diminished frequencies of naïve, immature, classical memory, activated memory, atypical memory and plasma cells. In addition, LBMI individuals showed significantly decreased frequencies of classical monocytes, myeloid DCs and plasmacytoid DCs and significantly increased frequencies of intermediate and non-classical monocytes and myeloid derived suppressor cells. BMI exhibited a positive correlation with B cell and NK cell counts. Our data, therefore, demonstrates that coexistent undernutrition in LTBI is characterized by the occurrence of a significant modulation in the frequency of innate and adaptive immune cell subsets.

Age-specific prevalence of TB infection among household contacts of pulmonary TB: Is it time for TB preventive therapy?

BACKGROUND: Household contacts (HHCs) of TB patients are at high risk of developing evidence of latent TB infection (LTBI) and active disease from the index patient. We estimated the age-specific prevalence of LTBI and the force of infection (FI), as a measure of recent transmission, among HHCs of active TB patients. METHODS: A cross-sectional analysis of HHCs of pulmonary TB patients enrolled in a prospective study, 'CTRIUMPh', was conducted at two sites in India. LTBI was defined as either a positive tuberculin skin test (induration ≥5 mm) or QuantiFERON-Gold in tube test (value ≥0.35 IU/ml) and was stratified by age. FI, which is a measure of recent transmission of infection and calculated using changes in age-specific prevalence rates at specific ages, was calculated. Factors associated with LTBI were determined by logistic regression models. RESULTS: Of 1020 HHCs of 441 adult pulmonary TB cases, there were 566 (55%) females and 289 (28%) children aged ≤15 y. While screening for the study 3% of HHC were diagnosed with active TB. LTBI prevalence among HHCs of pulmonary TB was 47% at <6 y, 53% between 6-14 y and 78% between 15-45 y. FI increased significantly with age, from 0.4 to 1.15 in the HHCs cohort (p=0.05). CONCLUSION: This study observed an increased prevalence of LTBI and FI among older children and young adults recently exposed to infectious TB in the household. In addition to awareness of coughing etiquette and general hygiene, expanding access to TB preventive therapy to all HHCs, including older children, may be beneficial to achieve TB elimination by 2035.

Burden of pulmonary tuberculosis in modern prison: A cross sectional prevalence survey from south India.

BACKGROUND: The risk of spread of Pulmonary Tuberculosis (PTB) disease depends on several factors. One important factor is the situational and environmental vulnerabilities of the prison setting. Study was conducted in central prison in Chennai, south state, India to estimate the prevalence of PTB disease in 2013. METHODS: All inmates aged 15 years and above were available during survey period screened for symptoms suggestive of PTB and X-ray taken chest PA view. Two sputum specimens were collected for smear and culture examination. All culture positive samples were used for drug sensitivity testing for first line anti-TB drugs. Information on demographic, life style characteristics, past history of PTB treatment were collected through pre-coded interview schedule. RESULTS: Of 1854 jail inmates were screened, prevalence of symptoms suggestive of PTB was 35% and it was dominated by males. Out of all screened 16 PTB cases are diagnosed and the estimated overall prevalence of PTB among prison inmates was 16/1854 (863/100,000 population). CONCLUSIONS: Prevalence PTB was 2.5 times higher as compared to prevalence of PTB in general population in the same areas, and 3.4 times higher as compared to national average.

Coexistent Helminth Infection-Mediated Modulation of Chemokine Responses in Latent Tuberculosis.

Coexistent helminth infections are known to modulate T cell and cytokine responses in latent infection with Mycobacterium tuberculosis However, their role in modulating chemokine responses in latent tuberculosis (LTB) has not been explored. Because chemokines play a vital role in the protective immune responses in LTB, we postulated that coexistent helminth infection could modulate chemokine production in helminth-LTB coinfection. To test this, we measured the levels of a panel of CC and CXC chemokines at baseline and following mycobacterial Ag or mitogen stimulation in individuals with LTB with (Strongyloides stercoralis +LTB+) or without S. stercoralis (S. stercoralis -LTB+) infection and in individuals without both infections, healthy controls (HC). At baseline (in the absence of a stimulus), S. stercoralis +LTB+ individuals exhibited significantly diminished production of CCL1, CCL2, CCL4, CCL11, CXCL9, CXCL10, and CXCL11 in comparison with S. stercoralis -LTB+ and/or HC individuals. Upon mycobacterial Ag stimulation, S. stercoralis +LTB+ individuals exhibited significantly diminished production of CCL1, CCL2, CCL4, CCL11, CXCL2, CXCL9, and CXCL10 in comparison with S. stercoralis -LTB+ and/or HC individuals. No differences were observed upon mitogen stimulation. Finally, after anthelmintic treatment, the baseline levels of CCL1, CCL2, CCL4, CCL11, and CXCL11 and mycobacterial Ag-stimulated levels of CCL1, CCL2, CCL11, CXCL2, and CXCL10 were significantly increased in S. stercoralis +LTB+ individuals. Thus, our data demonstrate that S. stercoralis +LTB+ individuals are associated with a compromised ability to express both CC and CXC chemokines and that this defect is at least partially reversible upon treatment. Hence, coexistent helminth infection induces downmodulation of chemokine responses in LTB individuals with likely potential effects on tuberculosis pathogenesis.

Altered levels of memory T cell subsets and common γc cytokines in Strongyloides stercoralis infection and partial reversal following anthelmintic treatment.

BACKGROUND: CD4+ and CD8+ T cells are central players in immunity to helminth infections. However, the role of T cell subsets in human helminth infections is not well understood. In addition, the common γc cytokines, IL-2, IL-4, IL-7, IL-9 and IL-15 play an important role in the maintenance of these CD4+ and CD8+ T cell subsets. METHODS: To examine the major T cell subsets and their association with the common γc cytokines, the absolute numbers of CD4+ and CD8+ naïve, central memory, effector memory and effector cells and the plasma levels of IL-2, IL-4, IL-7, IL-9 and IL-15 were measured in Strongyloides stercoralis (Ss) infected (INF, n = 60), helminth-uninfected (UN, n = 58) and in post treatment INF individuals. RESULTS: Ss infection is characterized by significantly increased absolute numbers of naïve and decreased absolute numbers of central and effector memory CD4+ T cells in comparison to UN individuals. No significant difference in the numbers of CD8+ T cell subsets was observed between the groups. The numbers of naïve cells and central memory CD4+ T cells were significantly reversed after anthelmintic treatment. Circulating levels of IL-2, IL-7 and IL-15 were significantly diminished, whereas the levels of IL-4 and IL-9 were significantly increased in INF compared to UN individuals. Following anthelminthic treatment, IL-2, IL-7 and IL-15 levels were significantly increased, while IL-4 and IL-9 levels were significantly decreased. Our data also showed a significant positive correlation between the levels of IL-7 and the numbers of central and effector memory CD4+ T cells. CONCLUSION: Ss infection is characterized by alterations in the absolute numbers of CD4+ T cell subsets and altered levels of common γc cytokines IL-2, IL-4, IL-7, IL-9 and IL-15; alterations which are partially reversed after anthelmintic treatment.

Elevated Systemic Levels of Eosinophil, Neutrophil, and Mast Cell Granular Proteins in Strongyloides Stercoralis Infection that Diminish following Treatment.

Infection with the helminth parasite Strongyloides stercoralis (Ss) is commonly clinically asymptomatic that is often accompanied by peripheral eosinophilia. Granulocytes are activated during helminth infection and can act as immune effector cells. Plasma levels of eosinophil and neutrophil granular proteins convey an indirect measure of granulocyte degranulation and are prominently augmented in numerous helminth-infected patients. In this study, we sought to examine the levels of eosinophil, neutrophil, and mast cell activation-associated granule proteins in asymptomatic Ss infection and to understand their kinetics following anthelmintic therapy. To this end, we measured the plasma levels of eosinophil cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, eosinophil major basic protein, neutrophil elastase, myeloperoxidase, neutrophil proteinase-3, mast cell tryptase, leukotriene C4, and mast cell carboxypeptidase-A3 in individuals with asymptomatic Ss infection or without Ss infection [uninfected (UN)]. We also estimated the levels of all of these analytes in infected individuals following definitive treatment of Ss infection. We demonstrated that those infected individuals have significantly enhanced plasma levels of eosinophil cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, eosinophil major basic protein, elastase, myeloperoxidase, mast cell tryptase, leukotriene C4, and carboxypeptidase-A3 compared to UN individuals. Following the treatment of Ss infection, each of these granulocyte-associated proteins drops significantly. Our data suggest that eosinophil, neutrophil, and mast cell activation may play a role in the response to Ss infection.

Type 2 diabetes - Tuberculosis co-morbidity is associated with diminished circulating levels of IL-20 subfamily of cytokines.

IL-20 subfamily of cytokines play an important role in both host defense mechanisms and glucose metabolism. Since, the interaction between tuberculosis (TB) and diabetes (DM) involves both of the above processes, we examined the association of IL-20 subfamily of cytokines in TB-DM co-morbidity. We examined circulating plasma cytokine levels in individuals with active TB with (PTB-DM) or without (PTB) diabetes and also those with latent TB with (LTB-DM) or without (LTB) diabetes. PTB-DM is characterized by diminished circulating levels of IL-19, IL-20, IL-22 and IL-24 but increased levels of IL-10. Similarly, LTB-DM was also characterized by diminished circulating levels of IL-10, IL-19, IL-20 and IL-24 but increased levels of IL-22. Moreover, there was a significant negative correlation of IL-10, IL-19, IL-20, IL-22 and IL-24 levels with hemoglobin A1C (HbA1c) levels in both PTB and/or LTB individuals. Finally, PTB is characterized by diminished levels of IL-19, IL-20, IL-22 and IL-24 in comparison to LTB individuals. Our data reveal that coincident diabetes in either PTB or LTB is characterized by decreased production of the IL-20 subfamily of cytokines and suggest that these cytokines might play an important role in pathogenesis or protection.

Diminished systemic and antigen-specific type 1, type 17, and other proinflammatory cytokines in diabetic and prediabetic individuals with latent Mycobacterium tuberculosis infection.

BACKGROUND: Diabetes mellitus type 2 (DM) is known to be a major risk factor for the development of active tuberculosis, although its influence on latent Mycobacterium tuberculosis infection (hereafter, "latent infection") remains poorly characterized. METHODS: We examined circulating plasma cytokine levels in individuals with latent infection with DM or pre-DM (ie, intermediate hyperglycemia) and compared them to levels in patients with latent infection and normal glycemic control. RESULTS: In persons with DM or pre-DM, latent infection is characterized by diminished circulating levels of type 1 (interferon γ, interleukin 2, and tumor necrosis factor α) and type 17 (interleukin 17F) cytokines. This was associated with decreased systemic levels of other proinflammatory cytokines (interleukin 1ß and interleukin 18) and the antiinflammatory cytokine interleukin 10 but not with decreased systemic levels of type 2 cytokines. Moreover, latently infected individuals with DM had diminished levels of spontaneous and M. tuberculosis antigen-specific levels of type 1 and type 17 cytokines when antigen-stimulated whole blood was examined. Finally, there was no significant correlation between the levels of any of the cytokines measured (with the exception of interleukin 22) with hemoglobin A1c levels. CONCLUSIONS: Our data reveal that latent infection in the presence of DM or pre-DM, is characterized by diminished production of cytokines, implicated in the control of M. tuberculosis activation, allowing for a potential immunological mechanism that could account for the increased risk of active tuberculosis in latently infected individuals with DM.