Cytokine and chemokine profiles in pulmonary tuberculosis with pre-diabetes.

Introduction: Tuberculosis (TB) remains a significant health concern in India, and its complexity is exacerbated by the rising occurrence of non-communicable diseases such as diabetes mellitus (DM). Recognizing that DM is a risk factor for active TB, the emerging comorbidity of TB and PDM (TB-PDM) presents a particular challenge. Our study focused on the impact of PDM on cytokine and chemokine profiles in patients with pulmonary tuberculosis TB) who also have PDM. Materials and methods: We measured and compared the cytokine (GM-CSF, IFN-γ, IL-1α/IL-1F1, IL-1ß/IL-1F2, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17/IL-17A, IL-18/IL-1F4, TNF-α) and chemokine (CCL1, CCL2, CCL3, CCL4, CCL11, CXCL1, CXCL2, CXCL9, CXCL10, and CXCL11) levels in plasma samples of TB-PDM, only TB or only PDM using multiplex assay. Results: We observed that PDM was linked to higher mycobacterial loads in TB. Patients with coexisting TB and PDM showed elevated levels of various cytokines (including IFNγ, TNFα, IL-2, IL-17, IL-1α, IL-1ß, IL-6, IL-12, IL-18, and GM-CSF) and chemokines (such as CCL1, CCL2, CCL3, CCL4, CCL11, CXCL1, CXCL9, CXCL10, and CXCL11). Additionally, cytokines such as IL-18 and GM-CSF, along with the chemokine CCL11, were closely linked to levels of glycated hemoglobin (HbA1c), hinting at an interaction between glycemic control and immune response in TB patients with PDM. Conclusion: Our results highlight the complex interplay between metabolic disturbances, immune responses, and TB pathology in the context of PDM, particularly highlighting the impact of changes in HbA1c levels. This emphasizes the need for specialized approaches to manage and treat TB-PDM comorbidity.

Plasma Immune Biomarkers Predictive of Progression to Active Tuberculosis in Household Contacts of TB Patients.

BACKGROUND: The progression from Mycobacterium tuberculosis infection to active tuberculosis (TB) disease varies among individuals, and identifying biomarkers to predict progression is crucial for guiding interventions. In this study, we aimed to determine plasma immune biomarker profiles in healthy household contacts of index pulmonary TB (PTB) patients who either progressed to TB or remained as non-progressors. METHODS: A cohort of household contacts of adults with PTB was enrolled, consisting of 15 contacts who progressed to TB disease and 15 non-progressors. Plasma samples were collected at baseline, 4 months, and 12 months to identify predictive TB progression markers. RESULTS: Our findings revealed that individuals in the progressor group exhibited significantly decreased levels of IFNγ, IL-2, TNFα, IL1α, IL1ß, IL-17A, and IL-1Ra at baseline, months 4 and 12. In contrast, the progressor group displayed significantly elevated levels of IFNα, IFNß, IL-6, IL-12, GM-CSF, IL-10, IL-33, CCL2, CCL11, CXCL8, CXCL10, CX3CL1, VEGF, Granzyme-B and PDL-1 compared to the non-progressor group at baseline, months 4 and 12. ROC analysis identified IFNγ, GM-CSF, IL-1Ra, CCL2 and CXCL10 as the most promising predictive markers, with an AUC of ≥90. Furthermore, combinatorial analysis demonstrated that GM-CSF, CXCL10 and IL-1Ra, when used in combination, exhibited high accuracy in predicting progression to active TB disease. CONCLUSIONS: Our study suggests that a specific set of plasma biomarkers GM-CSF, CXCL10 and IL-1Ra, can effectively identify household contacts at significant risk of developing TB disease. These findings have important implications for early intervention and preventive strategies in TB-endemic regions.

Relative contribution of biomedical, demographic, and socioeconomic factors to COVID-19 vaccine receipt in rural India.

BACKGROUND: In the first year of roll-out, vaccination for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevented almost 20 million deaths from coronavirus disease 2019 (COVID-19). Yet, little is known about the factors influencing access to vaccination at the individual level within rural poor settings of low-income countries. The aim of this study was to examine determinants of vaccine receipt in rural India. METHODS: A census of a rural village in Tamil Nadu was undertaken from June 2021 to September 2022. We surveyed 775 participants from 262 households. Household-level data on socioeconomic status (SES), water, sanitation, and hygiene practices, and individual-level demographic information, travel history, and biomedical data, including anthropometry, vital signs, and comorbidities, were collected. Logistic regression models with 5-fold cross-validation were used to identify the biomedical, demographic, and socioeconomic determinants of vaccine receipt and the timing of receipt within the first 30 days of eligibility. Vaccine ineligible participants were excluded leaving 659 eligible participants. There were 650 eligible participants with complete biomedical, demographic, and socioeconomic data. RESULTS: There were 68.0% and 34.0% of individuals (N = 650) who had received one and two vaccine doses, respectively. Participants with household ownership of a permanent account number (PAN) or ration card were 2.15 (95% CI:1.32-3.52) or 3.02 (95% CI:1.72-5.29) times more likely to receive at least one vaccine dose compared to households with no ownership of such cards. Participants employed as housewives or self-employed non-agricultural workers were 65% (95% CI:0.19-0.67) or 59% (95% CI:0.22-0.76) less likely to receive at least one vaccine dose compared to salaried workers. Household PAN card ownership, occupation and age were linked to the timing of vaccine receipt. Participants aged ≤18 and 45-60 years were 17.74 (95% CI:5.07-62.03) and 5.51 (95% CI:2.74-11.10) times more likely to receive a vaccine within 30 days of eligibility compared to 19-44-year-olds. Biomedical factors including BMI, vital signs, comorbidities, and COVID-19 specific symptoms were not consistently associated with vaccine receipt or timing of receipt. No support was found that travel history, contact with COVID-19 cases, and hospital admissions influenced vaccine receipt or timing of receipt. CONCLUSION: Factors linked to SES were linked to vaccine receipt, more so than biomedical factors which were targeted by vaccine policies. Future research should explore if government interventions including vaccine mandates, barriers to vaccine access, or peer influence linked to workplace or targeted vaccine promotion campaigns underpin these findings.

Helminth Infections and Diabetes: Mechanisms Accounting for Risk Amelioration.

The global prevalence of type 2 diabetes mellitus (T2D) is increasing rapidly, with an anticipated 600 million cases by 2035. While infectious diseases such as helminth infections have decreased due to improved sanitation and health care, recent research suggests a link between helminth infections and T2D, with helminths such as Schistosoma, Nippostrongylus, Strongyloides, and Heligmosomoides potentially mitigating or slowing down T2D progression in human and animal models. Helminth infections enhance host immunity by promoting interactions between innate and adaptive immune systems. In T2D, type 1 immune responses are suppressed and type 2 responses are augmented, expanding regulatory T cells and innate immune cells, particularly type 2 immune cells and macrophages. This article reviews recent research shedding light on the favorable effects of helminth infections on T2D. The potential defense mechanisms identified include heightened insulin sensitivity and reduced inflammation. The synthesis of findings from studies investigating parasitic helminths and their derivatives underscores promising avenues for defense against T2D.

Impact of Strongyloides stercoralis infection on complement activation in Type 2 diabetes mellitus: Insights from a clinical and anthelmintic intervention study.

BACKGROUND: Numerous studies indicate a potential protective role of helminths in diabetes mellitus (DM) progression. The complement system, vital for host defense, plays a crucial role in tissue homeostasis and immune surveillance. Dysregulated complement activation is implicated in diabetic complications. We aimed to investigate the influence of the helminth, Strongyloides stercoralis (Ss) on complement activation in individuals with type 2 DM (T2D). METHODOLOGY: We assessed circulating levels of complement proteins (C1q, C2, C3, C4, C4b, C5, C5a, and MBL (Lectin)) and their regulatory components (Factor B, Factor D, Factor H, and Factor I) in individuals with T2D with (n = 60) or without concomitant Ss infection (n = 58). Additionally, we evaluated the impact of anthelmintic therapy on these parameters after 6 months in Ss-infected individuals (n = 60). RESULTS: Ss+DM+ individuals demonstrated reduced levels of complement proteins (C1q, C4b, MBL (Lectin), C3, C5a, and C3b/iC3b) and complement regulatory proteins (Factor B and Factor D) compared to Ss-DM+ individuals. Following anthelmintic therapy, there was a partial reversal of these levels in Ss+DM+ individuals. CONCLUSION: Our findings indicate that Ss infection reduces complement activation, potentially mitigating inflammatory processes in individuals with T2D. The study underscores the complex interplay between helminth infections, complement regulation, and diabetes mellitus, offering insights into potential therapeutic avenues.

Elucidating systemic immune responses to acute and convalescent SARS-CoV-2 infection in children and elderly individuals.

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), a causative pathogen of the COVID-19 pandemic, affects all age groups. However, various studies have shown that COVID-19 presentation and severity vary considerably with age. We, therefore, wanted to examine the differences between the immune responses of children with COVID-19 and elderly COVID-19 individuals. METHODS: We analyzed cytokines, chemokines, growth factors, and acute phase proteins in acute and convalescent COVID-19 children and the elderly with acute and convalescent COVID-19. RESULTS: We show that most of the pro-inflammatory cytokines (interferon [IFN]γ, interleukin [IL]-2, tumor necrosis factor-α [TNFα], IL-1α, IFNα, IFNß, IL-6, IL-12, IL-3, IL-7, IL-1Ra, IL-13, and IL-10), chemokines (CCL4, CCL11, CCL19, CXCL1, CXCL2, CXCL8, and CXL10), growth factors (vascular endothelial growth factor and CD40L) and acute phase proteins (C-reactive protein, serum amyloid P, and haptoglobin) were decreased in children with acute COVID 19 as compared with elderly individuals. In contrast, children with acute COVID-19 exhibited elevated levels of cytokines- IL-1ß, IL-33, IL-4, IL-5, and IL-25, growth factors-fibroblast growth factor-2, platelet- derived growth factors-BB, and transforming growth factorα as compared with elderly individuals. Similar, differences were manifest in children and elderly with convalescent COVID-19. CONCLUSION: Thus, COVID-19 children are characterized by distinct cytokine/chemokine/growth factor/acute phase protein markers that are markedly different from elderly COVID-19 individuals.

Sex-specific differences in systemic immune responses in MIS-C children.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare manifestation of Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2) infection that can result in increased morbidity and mortality. Mounting evidence describes sex disparities in the clinical outcomes of coronavirus disease 2019 (COVID-19). However, there is a lack of information on sex-specific differences in immune responses in MIS-C. This study is an observational and cross-sectional study and we wanted to examine immune parameters such as cytokines, chemokines, acute phase proteins (APPs), growth factors, microbial translocation markers (MTMs), complement components and matrix metalloproteinases (MMPs) in MIS-C children, based on sex. Male children were associated with heightened levels of pro-inflammatory cytokines-IFNγ, IL-2, TNFα, IL-1α, IL-1ß, IL-6, IL-12, G-CSF and GM-CSF, chemokines-CCL2, CCL11, CXCL1, CXCL8 and CXCL10, acute phase proteins-α-2M, CRP, growth factors VEGF and TGFα, microbial translocation markers- iFABP, LBP, EndoCAb, complement components-C1q, MBL and C3 and matrix metalloproteinases MMP-8 and MMP-9 compared to female children with MIS-C. These results indicate that the heightened immune response in males is a characteristic feature of MIS-C. These findings might explain the differential disease pathogenesis in males compared to females with MIS-C and facilitate a deeper understanding of this disease.

Characterization of IL-10 Family of Cytokines in Acute and Convalescent COVID-19 Individuals.

Cytokines are major players in orchestrating inflammation, disease pathogenesis, and severity during COVID-19. Members of the interleukin (IL)-10 family of cytokines play important roles in regulating immune responses to various inflammatory and infectious diseases. However, the role of the IL-10 family of cytokines in COVID-19 remains elusive. Hence, we determined the plasma levels of the IL-10 family of cytokines (IL-10, IL-19, IL-20, IL-22, and IL-24) in 7 groups of COVID-19 individuals, based on days since real-time reverse transcriptase-polymerase chain reaction confirmation of SARS-CoV-2 infection. Our data show that the levels of IL-10, IL-19, IL-20, IL-22, and IL-24 cytokines decreased from days 15-30 to days 61-90 and plateaued thereafter. Severe COVID-19 patients exhibit increased plasma levels of IL-10, IL-19, IL-20, IL-22, and IL-24 compared to mild patients. Thus, our study provides evidence of alterations in the plasma levels of the IL-10 family of cytokines in convalescent COVID-19 individuals.

Hookworm infection induces glycometabolic modulation in South Indian individuals with type 2 diabetes.

Objectives: A number of epidemiological studies have demonstrated that there is an inverse relationship between helminth infections and diabetes mellitus, suggesting that helminth infection may have a positive effect on type 2 diabetes mellitus (T2DM). However, the association between hookworm infection and T2DM has barely been studied. Hence, we aimed to investigate and analyze the interaction and association between hookworm infection and T2DM. Methods: We examined the effect of hookworm infection on biochemical parameters, including plasma random blood glucose, glycated hemoglobin, and the plasma levels of pancreatic hormones, incretins, and adipokines in individuals with T2DM with (INF, n = 35) or without (UN, n = 35) hookworm infection. Moreover, we re-evaluated these analyte concentrations in a subset of INF individuals 6 months following anthelmintic therapy. Results: Compared to UN individuals, INF individuals had significantly lowered levels of random blood glucose and glycated hemoglobin. INF individuals also exhibited significantly diminished levels of adiponectin, adipsin, C-peptide, insulin, and glucagon compared to UN individuals. In contrast, INF individuals displayed substantially elevated levels of visfatin and incretins compared to UN individuals. Interestingly, this effect was not seen following anthelmintic treatment. Conclusion: Our study findings indicate that concomitant hookworm infection exerts a beneficial effect on glycometabolic parameters in T2DM.

Plasma chemokines CXCL10 and CXCL9 as potential diagnostic markers of drug-sensitive and drug-resistant tuberculosis.

Tuberculosis (TB) diagnosis still remains to be a challenge with the currently used immune based diagnostic methods particularly Interferon Gamma Release Assay due to the sensitivity issues and their inability in differentiating stages of TB infection. Immune markers are valuable sources for understanding disease biology and are easily accessible. Chemokines, the stimulant, and the shaper of host immune responses are the vital hub for disease mediated dysregulation and their varied levels in TB disease are considered as an important marker to define the disease status. Hence, we wanted to examine the levels of chemokines among the individuals with drug-resistant, drug-sensitive, and latent TB compared to healthy individuals. Our results demonstrated that the differential levels of chemokines between the study groups and revealed that CXCL10 and CXCL9 as potential markers of drug-resistant and drug-sensitive TB with better stage discriminating abilities.

Alterations of adipokines, pancreatic hormones and incretins in acute and convalescent COVID-19 children.

BACKGROUND: The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), accountable for Coronavirus disease 2019 (COVID-19), may cause hyperglycemia and additional systemic complexity in metabolic parameters. It is unsure even if the virus itself causes type 1 or type 2 diabetes mellitus (T1DM or T2DM). Furthermore, it is still unclear whether even recuperating COVID-19 individuals have an increased chance to develop new-onset diabetes. METHODS: We wanted to determine the impact of COVID-19 on the levels of adipokines, pancreatic hormones, incretins and cytokines in acute COVID-19, convalescent COVID-19 and control children through an observational study. We performed a multiplex immune assay analysis and compared the plasma levels of adipocytokines, pancreatic hormones, incretins and cytokines of children presenting with acute COVID-19 infection and convalescent COVID-19. RESULTS: Acute COVID-19 children had significantly elevated levels of adipsin, leptin, insulin, C-peptide, glucagon and ghrelin in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had elevated levels of adipsin, leptin, insulin, C-peptide, glucagon, ghrelin and Glucagon-like peptide-1 (GLP-1) in comparison to control children. On the other hand, acute COVID-19 children had significantly decreased levels of adiponectin and Gastric Inhibitory Peptide (GIP) in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had decreased levels of adiponectin and GIP in comparison to control children. Acute COVID-19 children had significantly elevated levels of cytokines, (Interferon (IFN)) IFNγ, Interleukins (IL)-2, TNFα, IL-1α, IL-1ß, IFNα, IFNß, IL-6, IL-12, IL-17A and Granulocyte-Colony Stimulating Factors (G-CSF) in comparison to convalescent COVID-19 and controls. Convalescent COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IL-1ß, IFNα, IFNß, IL-6, IL-12, IL-17A and G-CSF in comparison to control children. Additionally, Principal component Analysis (PCA) analysis distinguishes acute COVID-19 from convalescent COVID-19 and controls. The adipokines exhibited a significant correlation with the levels of pro-inflammatory cytokines. CONCLUSION: Children with acute COVID-19 show significant glycometabolic impairment and exaggerated cytokine responses, which is different from convalescent COVID-19 infection and controls.

Levels of Complement Components in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome.

Importance: Multisystem inflammatory syndrome in children (MIS-C) is a severe and unrestrained inflammatory response with multiorgan involvement, which occurs within a few weeks following the resolution of acute SARS-CoV-2 infection. The complement system is a vital part of the innate immune system and plays a role in COVID-19 pathogenesis. Objective: To examine and compare the levels of complement components and regulators along with complement activation products in the different clinical spectrum of children with SARS-CoV-2 and a control group. Design, Setting, and Participants: This cross-sectional study analyzed children with MIS-C admitted to a single hospital in India from June through September 2020. Eligible participants were children who were hospitalized of either sex, aged 1 to 18 years. Data were analyzed August 2022. Measures: Levels of complement components and regulators along with complement activation products in all the groups of children. Mann-Whitney U test and Kruskal-Wallis analysis were used to compare the complement component levels, and Spearman rank correlation analysis was used to describe the association between complement components and laboratory and biochemical parameters. Results: A total 145 children were included (median age, 5 years [range, 1 month-17 years); 84 [58%] male): 44 children with MIS-C, 33 with acute COVID-19 (reverse transcriptase-polymerase chain reaction [RT-PCR] positive), 47 with convalescent COVID-19 (immunoglobulin G-positive non-MIS-C) and 21 children for a control group (both serology and RT-PCR negative). Children with MIS-C and COVID-19 had higher levels of C1q (geometric mean [SD]: MIS-C, 61.5 [18.5] ng/mL; acute COVID-19, 56.9 [18.6] ng/mL; controls, 24.1 [3.3] ng/mL), C2 (MIS-C, 605.8 [219.7] ng/mL; acute COVID-19, 606.4 [167.7] ng/mL; controls, 255.9 [73.3] ng/mL), C3 (MIS-C, 318.2 [70.7] ng/mL; acute COVID-19, 237.7 [61.8] ng/mL; controls, 123.4 [15.7] ng/mL), C4b (MIS-C, 712.4 ng/mL; acute COVID-19, 640.7 ng/mL; controls, 351.5 ng/mL), C5 (MIS-C, 1487 ng/mL; acute COVID-19, 1364 ng/mL; controls, 561.9 ng/mL), C5a, (MIS-C, 2614.0 [336.2] ng/mL; acute COVID-19, 1826.0 [541.0] ng/mL; controls, 462.5 [132.4] ng/mL), C3b/iC3b (MIS-C, 3971.0 [635.1] ng/mL; acute COVID-19, 3702.0 [653.9] ng/mL; controls, 2039.0 [344.5] ng/mL), and factor B (MIS-C, 47.6 [7.8] ng/mL; acute COVID-19, 44.6 [6.3] ng/mL; controls, 27.5 [5.0] ng/mL), factor D (MIS-C, 44.0 [17.2] ng/mL; acute COVID-19, 33.8 [18.4] ng/mL; controls, 21.3 [6.1] ng/mL), and factor H (MIS-C, 53.1 [4.0] ng/mL; acute COVID-19, 50.8 [5.7] ng/mL; controls, 43.6 [3.8] ng/mL) in comparison with convalescent and control children. In addition, children with MIS-C had significantly elevated levels of C3 (318.2 [70.7] ng/mL vs 237.7 [61.8] ng/mL), C5a (2614 [336.2] ng/mL vs 1826 [541.0] ng/mL), and mannose-binding lectin (79.4 [12.4] ng/mL vs 69.6 [14.7] ng/mL) in comparison to children with acute COVID-19. Levels of some of these analytes at admission (ie, pretreatment) were more elevated in children with MIS-C who needed pediatric intensive care unit (PICU) support as compared with those who did not require PICU support, and in children with COVID-19 who developed moderate to severe disease compared with those who developed mild disease. Overall, MIS-C and acute COVID-19 were associated with the hyperactivation of complement components and complement regulators. Conclusions and Relevance: In this cross-sectional study, the complement system was associated with the pathogenesis of MIS-C and COVID-19 in children; complement inhibition could be further explored as a potential treatment option.

BCG vaccination induces enhanced humoral responses in elderly individuals.

BACKGROUND: Studies have reported the beneficial effects of Bacillus Calmette Guerin (BCG) vaccination, including non-specific cross-protection against other infectious diseases. METHODS: We investigated the impact of BCG vaccination on the frequencies of B cell subsets as well as total antibody levels in healthy elderly individuals at one month post vaccination. We also compared the above-mentioned parameters in post-vaccinated individuals to unvaccinated controls. RESULTS: Our results demonstrate that BCG vaccination induced enhanced frequencies of immature, classical and activated memory B cells and plasma cells and diminished frequencies of naïve and atypical memory B cells. BCG vaccination induced significantly increased levels of total IgG subclass isotypes compared to baseline. Similarly, all of the above parameters were significantly higher in vaccinated individuals compared to unvaccinated controls. CONCLUSION: BCG vaccination was associated with enhanced B cell subsets, suggesting its potential utility by enhancing heterologous immunity.

Cytokine upsurge among drug-resistant tuberculosis endorse the signatures of hyper inflammation and disease severity.

Tuberculosis (TB) elimination is possible with the discovery of accurate biomarkers that define the stages of infection. Drug-resistant TB impair the current treatment strategies and worsen the unfavourable outcomes. The knowledge on host immune responses between drug-sensitive and drug-resistant infection is inadequate to understand the pathophysiological differences and disease severity. The secreted proteins, cytokines display versatile behaviour upon infection with Mycobacterium tuberculosis (MTB) and their imbalances often tend to assist disease pathology than protection. Therefore, studying these soluble proteins across TB infection spectrum (drug-resistant TB, drug-sensitive TB, and latent TB) may unveil the disease mediated responses and unique stage specific cytokine signatures. Thus, we sought to determine the plasma cytokine levels from healthy, latently infected, drug-sensitive, and drug-resistant TB individuals. Our study revealed top 8 cytokines (IL-17, IL-1α, IL-2, IL-10, IL-5, IFN-γ, TNF-α and IL-6) and their biomarker abilities to discriminate different stages of infection.

QuantiFERON Supernatant-Based Host Biomarkers Predicting Progression to Active Tuberculosis Disease Among Household Contacts of Tuberculosis Patients.

BACKGROUND: The positive predictive value of tuberculin skin test and current generation interferon gamma release assays are very low leading to high numbers needed to treat. Therefore, it is critical to identify new biomarkers with high predictive accuracy to identify individuals bearing high risk of progression to active tuberculosis (TB). METHODS: We used stored QuantiFERON supernatants from 14 household contacts of index TB patients who developed incident active TB during a 2-year follow-up and 20 age and sex-matched non-progressors. The supernatants were tested for an expanded panel of 45 cytokines, chemokines, and growth factors using the Luminex Multiplex Array kit. RESULTS: We found significant differences in the levels of TB-antigen induced production of several analytes between progressors and non-progressors. Dominance analysis identified 15 key predictive biomarkers based on relative percentage importance. Principal component analysis revealed that these biomarkers could robustly distinguish between the 2 groups. Receiver operating characteristic analysis identified interferon-γ inducible protein (IP)-10, chemokine ligand (CCL)19, interferon (IFN)-γ, interleukin (IL)-1ra, CCL3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as the most promising predictive markers, with area under the curve (AUC) ≥90. IP-10/CCL19 ratio exhibited maximum sensitivity and specificity (100%) for predicting progression. Through Classification and Regression Tree analysis, a cutoff of 0.24 for IP-10/CCL19 ratio was found to be ideal for predicting short-term risk of progression to TB disease with a positive predictive value of 100 (95% confidence interval [CI] 85.8-100). CONCLUSIONS: The biomarkers identified in this study will pave way for the development of a more accurate test that can identify individuals at high risk for immediate progression to TB disease for targeted intervention.

Role of matrix metalloproteinases in multi-system inflammatory syndrome and acute COVID-19 in children.

Introduction: Multisystem Inflammatory Syndrome in children (MIS-C) is a serious inflammatory sequela of SARS-CoV2 infection. The pathogenesis of MIS-C is vague and matrix metalloproteinases (MMPs) may have an important role. Matrix metalloproteinases (MMPs) are known drivers of lung pathology in many diseases. Methods: To elucidate the role of MMPs in pathogenesis of pediatric COVID-19, we examined their plasma levels in MIS-C and acute COVID-19 children and compared them to convalescent COVID-19 and children with other common tropical diseases (with overlapping clinical manifestations). Results: Children with MIS-C had elevated levels of MMPs (P < 0.005 statistically significant) in comparison to acute COVID-19, other tropical diseases (Dengue fever, typhoid fever, and scrub typhus fever) and convalescent COVID-19 children. PCA and ROC analysis (sensitivity 84-100% and specificity 80-100%) showed that MMP-8, 12, 13 could help distinguish MIS-C from acute COVID-19 and other tropical diseases with high sensitivity and specificity. Among MIS-C children, elevated levels of MMPs were seen in children requiring intensive care unit admission as compared to children not needing intensive care. Similar findings were noted when children with severe/moderate COVID-19 were compared to children with mild COVID-19. Finally, MMP levels exhibited significant correlation with laboratory parameters, including lymphocyte counts, CRP, D-dimer, Ferritin and Sodium levels. Discussion: Our findings suggest that MMPs play a pivotal role in the pathogenesis of MIS-C and COVID-19 in children and may help distinguish MIS-C from other conditions with overlapping clinical presentation.

Unique cellular immune signatures of multisystem inflammatory syndrome in children.

The clinical presentation of MIS-C overlaps with other infectious/non-infectious diseases such as acute COVID-19, Kawasaki disease, acute dengue, enteric fever, and systemic lupus erythematosus. We examined the ex-vivo cellular parameters with the aim of distinguishing MIS-C from other syndromes with overlapping clinical presentations. MIS-C children differed from children with non-MIS-C conditions by having increased numbers of naïve CD8+ T cells, naïve, immature and atypical memory B cells and diminished numbers of transitional memory, stem cell memory, central and effector memory CD4+ and CD8+ T cells, classical, activated memory B and plasma cells and monocyte (intermediate and non-classical) and dendritic cell (plasmacytoid and myeloid) subsets. All of the above alterations were significantly reversed at 6-9 months post-recovery in MIS-C. Thus, MIS-C is characterized by a distinct cellular signature that distinguishes it from other syndromes with overlapping clinical presentations. Trial Registration: ClinicalTrials.gov clinicaltrial.gov. No: NCT04844242.

Strongyloidiasis stercoralis coinfection is associated with altered iron status biomarkers in tuberculous lymphadenitis.

Soil-transmitted helminth [mainly Strongyloidiasis stercoralis (Ss)] and tuberculous lymphadenitis (TBL) coinfection in humans is a significant public health problem. We have previously shown that TBL+Ss+ coinfection significantly alters diverse cytokine, matrix metalloproteinase, and tissue inhibitors of metalloproteinase profiles. However, no data is available to understand the influence of Ss coinfection in TBL disease with respect to iron status biomarkers. Hence, we have studied the effect of Ss coinfection on the circulating levels of iron status (ferritin, transferrin [TF], apotransferrin [ApoT], hepcidin, hemopexin) biomarkers in TBL disease. Our results show that TBL+Ss+ and/or TBL+Ss- individuals are associated with significantly altered biochemical and hematological (red blood cell (RBC) counts, hemoglobin (Hb), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) were decreased, and platelets were increased) parameters compared to TBL-Ss+ individuals. Our results also show that TBL+Ss+ coinfection is associated with diminished circulating levels of ferritin, ApoT, hepcidin, and hemopexin compared to TBL+Ss- individuals. TBL+Ss+ and TBL+Ss- groups are associated with altered iron status biomarkers (decreased ferritin [TBL+Ss+ alone] and increased TF, ApoT, hepcidin and hemopexin [TBL+Ss- alone]) compared to TBL-Ss+ group. The heat map expression profile and principal component analysis (PCA) analysis of iron status biomarkers were significantly altered in TBL+Ss+ compared to TBL+Ss- and/or TBL-Ss+ individuals. A significant correlation (positive/negative) was obtained among the biochemical and hematological parameters (white blood cells (WBC)/ferritin, TF, and hepcidin, mean corpuscular hemoglobin concentration (MCHC)/ferritin and hemopexin) with iron status biomarkers. Finally, receiver operating characteristic (ROC) analysis revealed that hemopexin was significantly associated with greater specificity and sensitivity in discriminating TBL+Ss+ and TBL+Ss- coinfected individuals. Thus, our data conclude that Ss coinfection is associated with altered iron status biomarkers indicating that coinfection might alter the host-Mtb interface and could influence the disease pathogenesis.

Prevalence of proximate risk factors of active tuberculosis in latent tuberculosis infection: A cross-sectional study from South India.

The prevalence of proximate risk factors for active tuberculosis (TB) in areas of high prevalence of latent tuberculosis infection (LTBI) is not clearly understood. We aimed at assessing the prevalence of non-communicable multi-morbidity focusing on diabetes mellitus (DM), malnutrition, and hypertension (HTN) as common risk factors of LTBI progressing to active TB. In a cross-sectional study, 2,351 adults (45% male and 55% female) from villages in the Kancheepuram district of South India were enrolled between 2013 and 2020. DM was defined as HbA1c >6.4%, undernutrition was defined as low body mass index (LBMI) <18.5 kg/m2, obesity was classified as BMI ≥25 kg/m2, HTN was reported as systolic pressure >130 mmHg, and LTBI was defined as positive (≥ 0.35 international units/ml) by QuantiFERON Gold In-Tube assay. A total of 1,226 individuals (52%) were positive for LTBI out of 2351 tested individuals. The prevalence of DM and pre-diabetes mellitus (PDM) was 21 and 35%, respectively, HTN was 15% in latent tuberculosis (LTB)-infected individuals. The association of DM [odds ratio (OR)]; adjusted odds ratio (aOR) (OR = 1.26, 95% CI: 1.13-1.65; aOR = 1.19, 95% CI: 1.10-1.58), PDM (OR = 1.11, 95% CI: 1.0-1.35), and HTN (OR = 1.28, 95% CI: 1.11-1.62; aOR = 1.18, 95% CI: 1.0-1.56) poses as risk factors of LTBI progression to active TB. The prevalence of LBMI 9% (OR = 1.07, 95% CI: 0.78-1.48) and obesity 42% (OR = 0.85, 95% CI: 0.70-1.03) did not show any statistically significant association with LTB-infected individuals. The present evidence of a high burden of multi-morbidity suggests that proximate risk factors of active TB in LTBI can be managed by nutrition and lifestyle modification.

Restoration of dendritic cell homeostasis and Type I/Type III interferon levels in convalescent COVID-19 individuals.

BACKGROUND: Plasmacytoid and myeloid dendritic cells play a vital role in the protection against viral infections. In COVID-19, there is an impairment of dendritic cell (DC) function and interferon secretion which has been correlated with disease severity. RESULTS: In this study, we described the frequency of DC subsets and the plasma levels of Type I (IFNα, IFNß) and Type III Interferons (IFNλ1), IFNλ2) and IFNλ3) in seven groups of COVID-19 individuals, classified based on days since RT-PCR confirmation of SARS-CoV2 infection. Our data shows that the frequencies of pDC and mDC increase from Days 15-30 to Days 61-90 and plateau thereafter. Similarly, the levels of IFNα, IFNß, IFNλ1, IFNλ2 and IFNλ3 increase from Days 15-30 to Days 61-90 and plateau thereafter. COVID-19 patients with severe disease exhibit diminished frequencies of pDC and mDC and decreased levels of IFNα, IFNß, IFNλ1, IFNλ2 and IFNλ3. Finally, the percentages of DC subsets positively correlated with the levels of Type I and Type III IFNs. CONCLUSION: Thus, our study provides evidence of restoration of homeostatic levels in DC subset frequencies and circulating levels of Type I and Type III IFNs in convalescent COVID-19 individuals.