Paragonimiasis Misdiagnosed as Pulmonary Tuberculosis: A Case Report
Study Identifies Potential Immune Biomarker For Pulmonary Tuberculosis: A Step Towards Early Detection
A recent study published in the Scientific Reports Journal examined immune responses in treatment-naive individuals with early-stage active pulmonary tuberculosis (TB) without clinical TB history. The researchers identified a potential immune biomarker associated with pulmonary TB in active patients compared to controls.
TB is a significant global public health concern due to its long-term effects, disabilities, fatalities, contagiousness, and insidious onset. Pakistan has an alarming incidence rate of 264/100,000 TB cases, ranking sixth out of 30 high-burden countries.
Mycobacterium tuberculosis (Mtb) is the primary causative agent of TB. Early immune responses against Mtb are crucial for confined infection, with cytokines and chemokines influencing inflammatory and anti-inflammatory responses.
Active TB is linked to higher pro-inflammatory and lower anti-inflammatory responses compared to chronic TB. Only a few transcriptional studies have examined unstimulated pulmonary TB peripheral blood mononuclear cells (PBMCs) for early detection of Mtb infection, with most studies using active, latent, or drug-treated cases.
The present study aimed to analyze naïve PBMCs from recently diagnosed active pulmonary TB patients within four to six weeks of clinical manifestations.
About the studyThis study enrolled 51 recently infected active pulmonary treatment-naïve TB patients and 25 healthy uninfected controls from Karachi, Pakistan. Recruitment was based on physical examination, clinical symptoms, and laboratory assessments.
The study used sputum analysis, Acid-fast Bacilli microscopy, GeneXpert testing, Mantoux tuberculin skin test (TST), and chest X-ray for patients with clinical TB symptoms. Fast immunochromatographic (IST) and ELISA tests were used for human immunodeficiency virus (HIV) testing, ensuring precise diagnosis and therapy.
The researchers selected 31 active pulmonary TB patients aged 15-55 years, excluding those with long-term, secondary, or relapsed Mtb, relapsed or extra-pulmonary TB, HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV) infections.
Blood samples from 31 TB patients and 25 controls were collected and processed within 15 minutes to isolate PBMCs using Ficoll Histopaque. The study used commercially available beta globulin (B2M) primers for complementary DNA (cDNA) preparation.
The RT2 Profiler polymerase chain reaction (PCR) Array was used to analyze 84 inflammatory genes, including chemokine, cytokine, and receptors. Three internal controls and five reference genes were used for quality control and normalization. Real-time PCR was performed according to the manufacturer's instructions.
Data analysis involved gene fold change, statistical significance, receiver operating characteristic (ROC) curve analysis, and visualization using GraphPad Prism and Qiagen software. Functional annotation and gene ontology were completed using ShinyGO.
ResultsThis study analyzed early transcriptional changes of unstimulated PBMCs from recently infected active pulmonary naive TB patients and controls. Most genes exhibited minimal to average expression patterns, but a few distinct gene clusters showed markedly different expression patterns between groups.
Patients with active TB displayed considerable differential expression patterns for 12 genes compared to controls. The cytokine transcripts that showed significant differential expression in unstimulated PBMCs from active TB patients were Interleukins-27 (IL-27), IL-15, IL-24, IL-2RA, and transforming growth factor beta (TGFβ).
Studies have demonstrated that particular T- helper cell type 1 (Th1) or T- helper cell type 2 (Th2) responses are the main drivers of cytokine profiles in naive and stimulated PBMCs from TB patients at various phases of disease.
A unique messenger RNA (mRNA) profile in active pulmonary TB patients was identified by comparing cytokines, transcription factors, and immune markers. Out of 84 transcripts, 5 gene signatures were identified, including upregulated IL-27, signal transducer and activator of transcription 1 (STAT1), toll-like receptor 4 (TLR4), and downregulated IL-24 and Cluster of differentiation 80 (CD80).
These signatures best discriminate between active pulmonary TB and uninfected controls of an area under the curve (AUC) value ranging from 0.9 to 1.
The authors used the bioinformatics approach to identify differentially expressed genes (DEGs) and their strong interactions among immune-related genes, such as IL-27, STAT1, and TLR4, involved in pro-inflammatory responses. The most distant genes were TGFβ and prostaglandin D2 receptor 2 (PTGDR2).
DEGs are primarily associated with critical biological processes such as immune activation, cell proliferation, and regulation, primarily abundant in cytokine activity and signaling pathways. According to the authors, more translational studies are needed to validate the current research findings within Pakistan and across different countries.
The immune profile observed in unstimulated PBMCs was not based on classical cytokines, but increased expression of IL-27, STAT1, IRF1, TLR4, and IL-15 may be crucial in the early pathogenic detection of TB. Further validation through translation studies is crucial in determining their utility as biomarkers.
ConclusionThis study identified unique molecular immune signature transcripts using unstimulated PBMCs (IL-27, STAT1, IRF1, TLR4, IL-15, IL-2RA, IL-24, TGF, CD28, CD80, nuclear factor of activated T-cells 1, and PTGDR2) that distinguish active pulmonary TB patients from uninfected controls.
Investigating the translation profile of these transcripts is crucial for the functional characterization and validation of biomarkers for early-stage TB infection.
Future works must focus on building global data on immune profiles of different ethnicities, developing medical tests for TB diagnosis at early stages, and devising treatment methods based on immunotherapies to avoid immune-related complications in TB patients.
Prior Tuberculosis In Children Linked To Poor Lung Function, Quality Of Life
October 10, 2022
2 min read
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Previous tuberculosis in Gambian children was significantly associated with impaired lung function and health-related quality of life, according to a cross-sectional comparative study published in Thorax.
"Lung development begins in utero and continues into early adulthood before declining from about 20 to 25 years of age. Consequently, early insults to the lungs have been shown to affect lung growth and development adversely," Esin Nkereuwem, MD, of the vaccines and immunity theme at the Medical Research Council Unit The Gambia at The London School of Hygiene & Tropical Medicine (MRCG at LSHTM) in Fajara, Gambia, and the Infectious and Tropical Diseases at The London School of Hygiene & Tropical Medicine in London, U.K., and colleagues wrote. "This has the potential to accelerate decline in lung function, and increase risk of chronic respiratory illnesses in later life, with consequent reduction in the [health-related quality of life]."
Data were derived from Nkereuwem E, et al. Thorax. 2022;doi:10.1136/thorax-2022-219085.
Researchers evaluated data of 68 children (median age, 8.9 years; 52.9% boys) who were diagnosed with tuberculosis at MRCG at LSHTM between January 2014 and December 2019 when aged younger than 15 years and who had completed pulmonary tuberculosis treatment at least 6 months prior to study enrollment. Researchers compared this group with 91 age-matched children (median age, 11.5 years; 62.6% boys) without a history of tuberculosis.
Researchers measured symptoms, spirometry and health-related quality of life using the Pediatric Quality of Life scale (PedsQL). Only 76.5% of those in the tuberculosis group and 94.5% of children in the control group met the quality criteria for spirometry.
Researchers observed lung function impairment among 38.5% of children with a history tuberculosis compared with 17.4% of children in the control group (P = .009). FEV1 (P < .001), FVC (P = .014) and FEV1/FVC (P < .001) z scores were all significantly lower among children with a history of tuberculosis compared with the control group.
Children in the tuberculosis group were more likely to report at least one recurrent respiratory symptom in the preceding 6 months (51.5% vs. 37.4%), including cough (30.9% vs. 22%), and they were more likely to report failure to gain weight (27.9% vs. 14.3%) compared with the control group.
Prior pulmonary tuberculosis (adjusted OR = 3.9; 95% CI, 1.1-15.1) and self-reported frequent or repeated chronic cough history (aOR = 19; 95% CI, 1.6-226) were both significantly associated with lung function impairment.
In addition, researchers observed significantly lower self-reported physical functioning scores on the PedsQL among those in the tuberculosis group (68.8% vs. 81.3%; P = .016), as well as lower scores for parent-reported physical, emotional, psychological, social and total health-related quality of life.
"Longitudinal studies to further characterize the evolution of symptoms and lung volumes after [tuberculosis] treatment completion in children are needed to help define and further characterize [post-tuberculosis lung disease] in children," the researchers wrote. "Finally, we recommend a more holistic approach to define [tuberculosis] treatment outcome which considers the evaluation and management of sequelae, especially in children, to improve health and well-being across the life course."
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Does Nutritional Support Benefit Adult Pulmonary Tuberculosis Patients?
In a recent study published in The Lancet Global Health journal, researchers evaluated the impact of nutritional support in Indian adults with microbiologically confirmed pulmonary tuberculosis. The study aimed to assess the impact of micro- and macronutrient supplementation on tuberculosis treatment success, outcomes, and mortality in the study cohort.
Tuberculosis remains a significant public health concern worldwide. In 2021, around three million people had tuberculosis and 494,000 human immunodeficiency virus (HIV)-negative tuberculosis patients died in India. Early diagnosis, comorbidity management, high-quality care, and thorough assessment are necessary to prevent tuberculosis-linked deaths.
Furthermore, undernutrition is a prevalent tuberculosis comorbidity in countries like India with high tuberculosis burden. Undernourished active tuberculosis patients are at risk of drug toxicity, disease relapse, and tuberculosis-associated mortalities.
Although World Health Organization (WHO) advises nutritional counseling, support, and assessment for tuberculosis, these guidelines are not always followed. While research has indicated that undernutrition management may lower tuberculosis mortality, there are conflicting results regarding the effects of micronutrient and macronutrient supplementation during tuberculosis treatment.
About the studyIn the present study, the investigators determined how nutritional support impacts tuberculosis treatment efficacy, tuberculosis-linked mortality, and other outcomes across the reducing activation of tuberculosis through the improvement of nutritional status (RATIONS) patient group over a six-month intervention period.
RATIONS is a cluster-randomized, field-based controlled trial analyzing the impact of nutritional support among household contacts of adult microbiologically confirmed pulmonary tuberculosis patients in Jharkhand, India.
Patients aged 18 years or older from 28 tuberculosis units of the National tuberculosis elimination program (NTEP) were enrolled in the study. The present trial was embedded within the NTEP in four districts of Jharkhand: West Singhbhum, Saraikela-Kharsawan, Ranchi, and East Singhbhum.
Household contacts of the tuberculosis patients were eligible for the trial if they resided with the index patient, shared the same kitchen, and did not have an active tuberculosis diagnosis.
Both subject populations in RATIONS, i.E., tuberculosis patients and their household contacts, received nutritional support in the form of micronutrient pills and food rations, i.E., 52 g of protein and 1200 kcal per day.
The patients were nutritionally supported for six months in case of drug-susceptible tuberculosis and 12 months in case of multidrug-resistant tuberculosis. Moreover, drug-susceptible tuberculosis patients were eligible for a six-month extension in nutrition support if they had a body mass index (BMI) below 18.5 kg/m2 at treatment completion.
The team recorded baseline diabetes status, modified Eastern cooperative oncology group (ECOG) performance status, and BMI. Subsequently, weight gain and clinical outcomes such as tuberculosis mortality, treatment success, alteration in performance status, and loss to follow-up were documented at six months.
Tuberculosis mortality predictors were evaluated leveraging Poisson and Cox regression employing adjusted hazard ratios (HRs) and adjusted incidence rate ratios (IRRs).
ResultsThe research team noted that 2,800 tuberculosis patients, including 1,979 males (70.7%) and 821 females (29.3%), with a mean age of 37.3 years for females and 41.5 years for males, were enrolled in the study between 16 August 2019 and 31 January 2021.
Most participants were from indigenous communities, known as scheduled tribes, engaged in physical labor, and received subsidized food rations from the public distribution system. Around 40% of the participants did not have formal education. Of 2,264 tested participants, 6 (0.3%), had tuberculosis-HIV co-infection, and of the total 2800 participants, 139 (5%), had diabetes.
Further, 2,291 (82.4%), participants had a BMI less than 18.5 kg/m2 and hence were underweight, and the BMI of 480 (17.3% ) participants were below 14 kg/m2 during enrolment. Mean BMI and weight were 16.4 kg/m2 and 42.6 kg for men and 16.2 kg/m2 and 36.1 kg for women, respectively.
In addition, of the 2676 participants, 54% or 1444 patients, demonstrated weight gain of around 5% of their baseline weight at two months. An association was found between decreased tuberculosis-linked mortality and relative and absolute weight gain during the initial two months across the Cox regression analysis.
Tuberculosis mortality predictors included BMI, baseline weight, hemoglobin, diabetes, and poor performance status. A 5% weight gain during the two months was associated with a reduced mortality risk.
At the six-month follow-up, five patients experienced treatment failure, 28 patients were lost to follow-up, 108 participants died due to tuberculosis, and 2,623 participants achieved treatment success. There was a median weight gain of 4.6 kg; however, 1,441 (54.8%) of 2,630 participants remained underweight.
ConclusionsThe study results showed that undernutrition was a serious, potentially lethal, and widely prevalent comorbidity among Indian pulmonary tuberculosis patients. While the study reported that baseline body weight was a tuberculosis mortality risk factor, they also noted that weight gain with nutritional support during the initial two months was related to a considerably lowered mortality risk during treatment.
The findings indicated that the nutritional support strategy through micronutrients and food baskets was a practical solution that was linked to performance status normalization, higher treatment success rates, lower loss to follow-up, and improved weight gain in most tuberculosis patients, compared to the NTEP data.
The researchers suggest that tuberculosis programs in India and other nations with high undernutrition and tuberculosis rates should routinely evaluate hemoglobin levels, performance status, and nutritional status during tuberculosis diagnosis, offer graded nutritional support, and provide close supervision and inpatient care referrals during the intensive phase of the illness.
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