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Understanding Tuberculosis From First Signs To Cure - Rolling Out

Understanding the causes, recognizing the signs, exploring treatment options, and implementing prevention strategies

Tuberculosis (TB) remains one of humanity's oldest and most persistent health challenges. Despite significant medical advances, this infectious disease continues to affect millions globally, with particularly devastating impacts in developing regions. Understanding TB's causes, recognizing its symptoms, knowing treatment options, and implementing prevention strategies are crucial steps in controlling this ancient yet evolving threat.

What causes tuberculosis?

At its core, tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, a rod-shaped bacterium with a unique waxy cell wall that contributes to its resilience and pathogenicity. This bacterial structure explains why TB can withstand harsh environmental conditions and resist many standard antibiotics.

The primary transmission route occurs through airborne particles. When someone with active TB coughs, sneezes, speaks, or even sings, they release microscopic droplets containing the bacteria. These droplets can remain suspended in the air for hours, particularly in poorly ventilated spaces. Individuals breathing this contaminated air may then become infected if the bacteria reach their lungs.

However, not everyone exposed to TB bacteria develops the disease. The human immune system often creates a barrier around the bacteria, forming what medical professionals call a granuloma. This immune response effectively walls off the infection, preventing symptoms and disease progression. This state is known as latent TB infection.

Several factors influence whether exposure leads to infection and whether infection progresses to active disease:

Proximity and duration of contact with an infected person Concentration of bacteria in the air Immune status of the exposed individual Nutritional health of the exposed person Presence of other medical conditions, particularly HIV

The distinction between latent TB infection and active TB disease remains crucial. In latent TB, the bacteria remain dormant, causing no symptoms and remaining non-contagious. However, approximately 5-10% of those with latent infections eventually develop active TB disease when their immune system can no longer contain the bacteria.

Risk factors for progression from latent to active TB include:

Recent infection (within the past two years) HIV infection and other immunocompromising conditions Substance abuse, particularly injection drugs Certain medical treatments that suppress immunity Young age (under 5) or advanced age (over 65) Diabetes mellitus End-stage renal disease Certain cancers, particularly head and neck cancers Malnutrition and low body weight

The bacterium's remarkable adaptability has led to the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. These resistant forms develop when patients receive inadequate treatment, stop treatment prematurely, or when healthcare providers prescribe inappropriate medication regimens.

Recognizing the signs and symptoms

Tuberculosis primarily affects the lungs (pulmonary TB), but can invade other body systems (extrapulmonary TB), including the kidneys, spine, brain, and lymph nodes. The symptoms vary depending on which organs are affected.

Pulmonary TB typically produces symptoms that develop gradually over weeks or months:

Persistent cough lasting three weeks or longer, often producing blood-tinged sputum Chest pain, particularly while breathing or coughing Unintentional weight loss despite normal or increased appetite Fatigue and weakness that interferes with daily activities Fever that typically rises in the evening, often accompanied by night sweats Loss of appetite leading to nutritional deficiencies Chills and cold sweats, particularly at night

These symptoms may initially be mild, allowing individuals to dismiss them as a common cold or bronchitis. This delayed recognition contributes to ongoing transmission before diagnosis.

Extrapulmonary TB presents with symptoms specific to the affected organ system:

TB meningitis (brain and spinal cord): Headaches, confusion, neck stiffness TB lymphadenitis (lymph nodes): Swollen, often painless lymph nodes, usually in the neck Skeletal TB: Back pain, joint destruction, particularly in the spine (Pott's disease) Genitourinary TB: Painful urination, blood in urine, pelvic pain Miliary TB (disseminated throughout body): Widespread symptoms, often severe

Children with TB often present differently than adults, showing:

Poor weight gain or failure to thrive Reduced playfulness and activity Persistent fever without clear cause Enlarged lymph nodes, particularly in the neck

Elderly patients may show atypical presentations, sometimes with minimal respiratory symptoms but pronounced confusion, decreased appetite, or generalized weakness, making diagnosis particularly challenging.

Diagnosing TB involves several approaches:

Tuberculin skin test (TST) or Mantoux test, which measures immune response to TB proteins Interferon-gamma release assays (IGRAs), blood tests that detect TB infection Chest X-rays to identify characteristic lung changes Sputum microscopy and culture to detect and grow the bacteria Nucleic acid amplification tests (NAATs) for rapid identification of the bacteria Tissue biopsies for extrapulmonary TB

Early detection remains critical for effective treatment and preventing transmission. Individuals with persistent coughs lasting more than three weeks, especially when accompanied by other symptoms, should seek medical evaluation.

Modern treatment approaches

The treatment landscape for tuberculosis has evolved significantly since the discovery of streptomycin in 1943, the first antibiotic effective against TB. Today's treatment approaches balance effectiveness, duration, side effects, and the growing challenge of drug resistance.

Standard treatment for drug-susceptible TB follows a two-phase approach:

Initial intensive phase (2 months): Combination of four first-line drugs—isoniazid, rifampin, ethambutol, and pyrazinamide Continuation phase (4 months): Usually isoniazid and rifampin

This lengthy treatment duration creates adherence challenges. To address this, Directly Observed Therapy (DOT) programs have become standard practice, where healthcare workers observe patients taking their medications to ensure compliance.

For drug-resistant forms, treatment becomes more complex:

MDR-TB requires 9-20 months of treatment with second-line drugs, which often cause more severe side effects XDR-TB demands even more complex regimens, sometimes lasting two years or more Newer medications like bedaquiline, delamanid, and pretomanid offer hope for resistant cases

Common side effects of TB medications include:

Liver inflammation and potential damage Peripheral neuropathy (nerve damage) Vision changes, particularly with ethambutol Gastrointestinal disturbances Joint pain, especially with pyrazinamide

Beyond medications, supportive care plays a vital role in TB treatment:

Nutritional support to counter weight loss and support immune function Management of respiratory symptoms Psychological support for the lengthy treatment journey Addressing social factors that might impede treatment completion

Recent research has introduced shorter treatment regimens for some patients, potentially reducing the standard six-month regimen to four months for certain forms of drug-susceptible pulmonary TB. These shorter regimens may improve completion rates while maintaining effectiveness.

Surgical interventions occasionally become necessary, particularly for drug-resistant cases or when TB creates structural damage to organs. Procedures may include:

Removal of severely damaged lung tissue Drainage of TB abscesses Stabilization of spine in cases of vertebral TB

The treatment success rate for drug-susceptible TB exceeds 85% in most settings with proper adherence. However, MDR-TB and XDR-TB success rates remain significantly lower, highlighting the urgent need for new treatment approaches and improved patient support systems.

Prevention strategies: Individual to global

Preventing tuberculosis requires a multi-layered approach spanning individual measures to global public health initiatives. These strategies focus on breaking the transmission chain, identifying and treating latent infections, and creating environments resistant to TB spread.

At the individual level, several measures reduce TB risk:

Prompt diagnosis and treatment of active cases to prevent transmission Avoiding close, prolonged contact with known TB patients until they become non-infectious Maintaining good overall health through proper nutrition and management of conditions that weaken immunity Seeking medical evaluation for persistent coughs or unexplained weight loss Completing full treatment courses if diagnosed with TB

For healthcare settings, infection control measures include:

Early identification and isolation of suspected TB cases Proper ventilation systems with negative pressure rooms for TB patients Use of ultraviolet germicidal irradiation in high-risk areas Personal protective equipment for healthcare workers Regular screening of healthcare workers for TB infection

Bacillus Calmette-Guérin (BCG) vaccination plays a critical role in TB prevention in many countries. This vaccine:

Provides 80% protection against severe forms of TB in children, including TB meningitis Offers variable protection against pulmonary TB in adults Remains widely administered in countries with high TB prevalence Is not routinely given in countries with low TB rates due to its limited effectiveness against pulmonary TB and potential interference with TB testing

For contacts of TB patients and others at high risk, treating latent TB infection prevents progression to active disease. Treatment options include:

Isoniazid for 6-9 months Rifampin for 4 months Isoniazid plus rifapentine for 3 months

Public health systems focus on systematic approaches:

Active case finding in high-risk populations Contact tracing to identify exposed individuals Surveillance systems to monitor TB trends and outbreaks Integration of TB and HIV services, given their synergistic relationship

Environmental factors significantly influence TB transmission. Addressing these includes:

Improved housing conditions to reduce overcrowding Better ventilation in communal spaces Access to natural light, which contains UV radiation that kills TB bacteria Reduction of indoor air pollution from cooking fires and other sources

Socioeconomic factors play a profound role in TB prevalence. Addressing these requires:

Poverty reduction initiatives Improved access to healthcare Nutritional support programs Educational campaigns about TB symptoms and transmission

The global fight against TB requires coordinated international efforts:

Funding for TB programs in high-burden countries Research for new vaccines, diagnostics, and treatments Cross-border TB control initiatives Support for countries with limited healthcare infrastructure

Despite these multifaceted prevention strategies, TB elimination faces significant challenges:

The reservoir of latent TB infection in approximately one-quarter of the global population Increasing drug resistance The HIV epidemic, which dramatically increases TB susceptibility Socioeconomic inequalities that facilitate TB transmission Disruptions to healthcare systems during crises like the COVID-19 pandemic

Tuberculosis sits at the intersection of medical science, public health policy, and social determinants of health. Its persistence despite available prevention and treatment options highlights the complex interplay of biological, social, and economic factors that maintain its global presence.

As healthcare systems continue evolving, the approach to TB must similarly advance—incorporating new technologies, addressing persistent inequalities, and strengthening healthcare infrastructure globally. Only through comprehensive efforts addressing both the pathogen and the conditions that enable its spread can we make meaningful progress against this ancient disease.

Understanding tuberculosis—its causes, symptoms, treatment, and prevention—empowers individuals and communities to participate actively in TB control efforts. With continued attention and resources, TB elimination remains a challenging but achievable global health goal.

How Accurate Are Low-complexity Manual Nucleic Acid Amplification Tests For Detecting Pulmonary Tuberculosis In Children?

Key messages

- There is limited evidence that LC-mNAATs can correctly identify pulmonary tuberculosis in children.

- Further studies are needed to assess the accuracy of LC-mNAATs among children.

Why is improving the diagnosis of pulmonary tuberculosis among children important?

Tuberculosis in children is frequently under-reported due to the difficulties associated with diagnosing the disease. Early detection and treatment of tuberculosis in children is vital for a timely and effective cure. However, recognising tuberculosis early is difficult due to its varied forms and symptoms, and challenges with producing phlegm (mucus coughed up from the lungs). In addition, bacterial levels in samples are lower than in adults. False-positive results can cause unnecessary anxiety, and children will be followed up, requiring time and resources. These children may also start tuberculosis treatment with severe side effects. False-negative results may result in missed cases, leading to the spread of the disease. Children with false-negative results may also develop severe forms of tuberculosis, leading to death due to delayed diagnosis.

What are low-complexity manual nucleic acid amplification tests for detecting tuberculosis?

One of the tests used for detecting tuberculosis is TB-LAMP (loop-mediated isothermal amplification), which belongs to a category known as low-complexity manual nucleic acid amplification tests (LC-mNAATs). These tests can be used in places with relatively simple infrastructure, similar to what is needed for sputum microscopy (microscope examination of mucus coughed up from the lungs). They are more accurate than tests with sputum or other respiratory samples, even when the bacterial count is low, and give results in a few hours. At present, there is a lack of evidence on the accuracy of the TB-LAMP test in detecting tuberculosis in children.

What did we want to find?

We wanted to find out how accurate LC-mNAATs are for detecting pulmonary tuberculosis in children presumed to have pulmonary tuberculosis and compare the accuracy with Xpert MTB/RIF Ultra and smear microscopy.

What did we do?

We searched for studies that investigated the accuracy of LC-mNAATs in detecting pulmonary tuberculosis in children and examined the results of relevant studies.

What did we find?

We included four studies (303 participants, 25 children with tuberculosis) that evaluated TB-LAMP. One study compared the accuracy of TB-LAMP and Xpert MTB/RIF Ultra, and three studies also used smear microscopy. These studies used multiple respiratory and non-respiratory specimens to detect tuberculosis. All studies used culture as the reference standard, the best available way of identifying the presence of tuberculosis.

Respiratory samples

Three studies (67 children, eight positive for tuberculosis) used respiratory samples (sputum (phlegm), bronchoalveolar lavage (⁠fluid obtained after washing the airway and lungs), and tracheal aspirate (fluid obtained from the windpipe)). The results indicate that 60% to 100% of children with tuberculosis will be identified as positive by the TB-LAMP test, and 95% to 100% of children without tuberculosis will be identified as negative by the test.

Gastric aspirate (fluid obtained from the stomach using a tube)

Three studies used gastric aspirate samples (176 children, 14 positive for pulmonary tuberculosis). The results indicate that 64% of children with tuberculosis will be identified as positive by the TB-LAMP test, and 35% to 87% of children without tuberculosis will be identified as negative by the test.

Gastric lavage (fluid obtained from the stomach using a tube after a wash)

One study with 60 children (three positive for tuberculosis) evaluated gastric lavage. For every 1000 children tested, if 100 had tuberculosis according to culture, 135 would be TB-LAMP positive, of which 99 would have tuberculosis, and 36 would not have tuberculosis; 865 would be TB-LAMP negative, of which 864 would not have tuberculosis, and one would have tuberculosis.

Nasopharyngeal aspirate (fluid obtained from the back of the nose and throat)

One study (144 children, 12 positive for tuberculosis) evaluated nasopharyngeal aspirate. For every 1000 children tested, if 100 had tuberculosis according to culture, 71 would be TB-LAMP positive, of which 12 would have tuberculosis, and 59 would not have tuberculosis; 929 would test negative, of which 921 would not have tuberculosis, and eight would have tuberculosis.

Stool

One study evaluated stool specimens (144 children, seven positive for pulmonary tuberculosis). For every 1000 children tested, if 100 had tuberculosis according to culture, 171 would be TB-LAMP positive, of which 99 would have tuberculosis, and 72 would not have tuberculosis; 829 would test negative, of which 828 would not have tuberculosis, and one child would have tuberculosis.

What are the limitations of the evidence?

We did not find any study that used a composite reference standard (the results of different tests are combined and considered as a confirmatory test). Since culture is not the best way to determine the disease in children, our evidence is limited. The results come from four studies with a small number of children, and the findings are likely to change as more studies become available.

How up-to-date is this evidence?

The evidence is up-to-date to October 2023.

Citation

Inbaraj LR, Sathya Narayanan MK, Daniel J, Srinivasalu VA, Bhaskar A, Daniel BD, Epsibha T, Scandrett K, Rajendran P, Rose W, Korobitsyn A, Ismail N, Takwoingi Y. Low-complexity manual nucleic acid amplification tests for pulmonary tuberculosis in children. Cochrane Database of Systematic Reviews 2025, Issue 6. Art. No.: CD015806. DOI: 10.1002/14651858.CD015806.Pub2.

Study Identifies Potential Immune Biomarker For Pulmonary Tuberculosis - News-Medical.net

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. 

Study: Identification of immune biomarkers in recent active pulmonary tuberculosis. Image Credit: dokurose/Shutterstock.Com Background

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 study

This 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.

Results

This 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. 

Conclusion

This 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.

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