Tuberculosis (TB) remains one of the deadliest infectious diseases worldwide, even in an age of remarkable medical advancements. Every year, an estimated 10 million people develop TB and 1.5 million lives are lost to the disease, making it the leading cause of death from a single infectious agent, even surpassing HIV/AIDS. Despite being preventable and curable, TB continues to impose a heavy burden, particularly in low- and middle-income countries, but it is a disease without borders, present across the entire globe.
Alarmingly, TB is also a leading cause of death among people with HIV and a major driver of antimicrobial resistance (AMR) worldwide, further complicating public health efforts. The emergence of multidrug-resistant and extensively drug-resistant TB strains poses a critical challenge to global TB control programs.
While the medical community has made significant strides in TB control through improved diagnostics, vaccines and treatment regimens, millions still lack access to early diagnosis and effective therapy. Rising cases of drug-resistant TB have added a new layer of complexity, threatening global health security.
This article provides a comprehensive understanding of TB including its causes, types, risk factors, pathophysiology, signs and symptoms, and complications.
What is Tuberculosis and What Causes It?
Tuberculosis (TB) is a serious, communicable disease that primarily targets the lungs but can also affect other organs and tissues throughout the body. It is classified as an airborne infectious disease, meaning it spreads from person to person through tiny droplets released into the air when an infected individual coughs, sneezes or even talks.1
The disease is caused by bacteria belonging to the Mycobacterium tuberculosis complex, a group of closely related bacterial species.2 The primary human pathogen is Mycobacterium tuberculosis, responsible for the majority of TB cases worldwide.
Another significant species is Mycobacterium bovis, which typically causes tuberculosis in cattle but can also infect humans, usually through the consumption of unpasteurized dairy products or direct contact with infected animals. In addition to these, Mycobacterium africanum and Mycobacterium canettii are rare causes of TB, predominantly found in certain regions of Africa.
Several other animal-associated pathogens have been recognized to cause zoonotic TB (TB transmitted from animals to humans). These include:
◦ Mycobacterium caprae, primarily found in cattle,
◦ Mycobacterium microti, affecting rodents,
◦ Mycobacterium pinnipedii, which infects seals.3
Active TB occurs when M. tuberculosis bacteria are actively multiplying in the body, leading to symptoms such as persistent cough, fever, night sweats, chest pain and weight loss. This form is contagious and requires urgent antibiotic treatment. In contrast, inactive TB or latent TB infection (LTBI), happens when the bacteria remain dormant without causing symptoms or spreading to others. However, individuals with latent TB are at risk of developing active TB if their immune system weakens. Active TB is typically diagnosed using chest X-rays and sputum tests, while latent TB is detected through tuberculin skin tests (TST) or interferon-gamma release assays (IGRAs). Treatment of latent TB focuses on preventing its progression to active disease.
Types of Tuberculosis
Tuberculosis (TB) can present in different forms depending on the site of infection, the strength of the immune system and drug resistance patterns.
1. Pulmonary Tuberculosis (PTB)
Pulmonary tuberculosis is the most common form of TB, affecting the lungs. It occurs when Mycobacterium tuberculosis enters the lungs, often through inhalation and begins to infect the tissue. In immunocompetent individuals, lung involvement occurs in 79% to 87% of cases, while in immunocompromised individuals, such as those with HIV, the rate is slightly lower (70% to 92%). Initially, the infection may not cause symptoms, but after 4 to 6 weeks, mild fever, malaise and hypersensitivity reactions can develop. In most cases, the infection remains localized and controlled by the body’s immune system. However, complications like tuberculous pleurisy or enlargement of lymph nodes can occur. If the infection spreads through bloodstream (hematogenous dissemination), it can result in both pulmonary and extrapulmonary disease. Radiologically, old infections may show Ghon’s complex, a characteristic feature of TB.4,5
2. Extrapulmonary Tuberculosis (EPTB)
Extrapulmonary tuberculosis refers to TB that affects organs outside the lungs such as the lymph nodes, pleura, bones or even the brain. Although less common than pulmonary TB, EPTB is a significant public health issue, accounting for around 21.5% of all TB cases globally. EPTB is more prevalent in immuno-compromised individuals and those with conditions like HIV. Risk factors include age extremes, gender (more common in females), migration from high-incidence TB areas, and immunosuppression. Though EPTB is less transmissible than pulmonary TB, it is still clinically important and often underreported in TB control programs. Common sites of infection include the lymph nodes and pleura, but it can affect virtually any organ. The clinical presentation can be varied and may involve nonspecific symptoms, making diagnosis challenging.4,6,7
3. Miliary Tuberculosis (Miliary TB)
Miliary tuberculosis is a rare but serious form of disseminated TB where the bacteria spread throughout the body via the bloodstream. It is characterized by tiny tubercles in organs, which appear like millet seeds, hence the name “miliary.” This form of TB is an emergency due to its rapid progression and high mortality if left untreated. It can affect any organ, with common involvement of the liver, lungs and spleen. Diagnosis is often made through chest X-ray, which shows multiple small opacities. A CT scan may be used for further evaluation and lumbar puncture is essential if there is suspicion of CNS involvement. Early initiation of treatment with first-line anti-TB drugs is crucial, and monitoring for complications such as respiratory distress or liver injury is necessary.4,8
4. Drug-Resistant Tuberculosis (Drug-Resistant TB)
Drug-resistant tuberculosis occurs when the M. tuberculosis bacteria become resistant to one or more of the drugs commonly used in treatment. This form of TB can take several forms, including mono-resistant TB (resistant to one drug), poly-resistant TB (resistant to at least two drugs), multidrug-resistant TB (MDR-TB, resistant to both isoniazid and rifampin) and extensively drug-resistant TB (XDR-TB, resistant to multiple drugs, including second-line options). MDR-TB and XDR-TB are particularly concerning as they require longer treatment regimens with second-line drugs, which are more expensive and less effective. Delays in diagnosing drug resistance can worsen the disease and increase transmission. The main transmission route for drug-resistant TB remains the same as for drug-susceptible TB, but with the added challenge of limited treatment options.4,9
5. Latent Tuberculosis Infection (LTBI)
Latent tuberculosis infection refers to a state where a person is infected with M. tuberculosis but does not show symptoms of active disease. People with LTBI are not contagious, but they harbor the bacteria in their body, which can become active at any time, especially under conditions of immunosuppression. About a quarter of the global population is estimated to be infected with LTBI. While most individuals with LTBI never develop active TB, a small fraction (~5% to 15%) will experience reactivation, often within 2 to 5 years of infection. Reactivation risk is higher in individuals with weakened immune systems particularly those with HIV, diabetes, chronic renal failure or those on immunosuppressive therapy. LTBI serves as a major reservoir for new cases of active TB, making screening and preventive treatment crucial, especially for high-risk groups.4,10
Risk Factors for Tuberculosis (TB) Transmission and Development
Tuberculosis (TB) is influenced by a variety of factors that can increase the likelihood of infection and disease progression. These risk factors include both individual and environmental conditions, as well as socioeconomic and health system-related issues.11,12
1. Bacillary Load: Higher concentrations of Mycobacterium tuberculosis in the sputum increase the risk of transmission to others.
2. Proximity to an Infectious Case: Close contacts, such as household members and healthcare workers, are more likely to contract TB from an infected individual.
3. Immunosuppressive Conditions (e.g., HIV): Conditions like HIV and immunosuppressive treatments weaken the immune system, making it easier for TB to develop.
4. Malnutrition: Malnutrition weakens the immune system, increasing the likelihood of TB infection and disease progression.
5. Young Age (especially under 5): Children, especially those under five, are at higher risk of contracting TB due to their developing immune systems.
6. Healthcare Workers: Healthcare workers are at greater risk of exposure to TB due to frequent contact with infected patients.
7. Socioeconomic and Behavioral Factors (e.g., overcrowding, poor nutrition): Living in conditions with overcrowding, poor nutrition and limited access to healthcare increases vulnerability to TB.
8. Tobacco Smoke: Smoking damages the lungs and weakens the immune system, increasing the likelihood of contracting TB.
9. Alcohol Use: Excessive alcohol use compromises the immune system and increases the risk of developing active TB.
10. Indoor Air Pollution: Exposure to smoke from cooking fuels and other indoor pollutants can damage lung function and increase TB risk.
11. Indigenous/Aboriginal Populations: These populations face higher TB risks due to socioeconomic disparities, co-existing conditions and genetic factors.
12. Health System Issues (e.g., delays in diagnosis): Delays in diagnosis and treatment can extend the infectious period, facilitating transmission.
13. Limited Healthcare Access: Limited access to healthcare services increases the risk of undiagnosed and untreated TB, leading to further spread.
14. Co-existing Conditions (e.g., HIV, diabetes, kidney disease): Individuals with other conditions, such as HIV, diabetes, severe kidney disease are at increased risk of contracting TB and experiencing worse outcomes. It can weaken the immune system, making individuals more susceptible to TB infection and complicating its treatment.
15. Substance Use (e.g., Injection Drug Use): Substance use, including injection drug use, weakens the immune system and can increase the likelihood of TB infection.
16. Organ Transplants: Organ transplant recipients are at higher risk of TB due to the immunosuppressive treatments they receive to prevent organ rejection.
17. Head and Neck Cancer: Patients with head and neck cancer, especially those undergoing radiation or chemotherapy, are more susceptible to TB.
18. Silicosis: Silicosis, a lung disease caused by inhaling silica dust, damages the lungs and increases the risk of TB infection.
19. Low Body Weight: Low body weight or malnutrition weakens the immune system, making individuals more vulnerable to TB infection.
Pathophysiology of Tuberculosis
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis and its progression within the human body follows a well-defined path that begins with transmission and can culminate in severe pulmonary and systemic disease if untreated.13,14
1. Transmission via Aerosolized Droplets: TB spreads when an individual with active disease expels M. tuberculosis into the air through coughing, sneezing or even speaking. The released tiny aerosol droplets, containing live bacteria, can be inhaled by people nearby, making TB a highly contagious airborne disease.
2. Initial Encounter and Immune Response: Upon inhalation, the droplets travel deep into the respiratory tract, reaching the alveoli of the lungs. Here, the host’s innate immune system attempts to neutralize the bacteria. Alveolar macrophages recognize and engulf the bacilli through a process called phagocytosis. However, M. tuberculosis has evolved mechanisms to avoid destruction by inhibiting the fusion of phagosomes with lysosomes inside macrophages, allowing it to survive and replicate intracellularly.
3. Amplification and Recruitment of Immune Cells: As infected macrophages accumulate, they release signaling molecules such as cytokines and vascular endothelial growth factor (VEGF). These molecules attract other immune cells like neutrophils, natural killer (NK) cells, dendritic cells and additional macrophages to the infection site, initiating a broader innate immune response. Despite these defenses, the bacteria may continue to replicate within the protected environment of host cells.
4. Formation of Granuloma: The dendritic cells migrate to nearby lymph nodes and activate T-helper (TH1) cells and other lymphocytes. These activated immune cells return to the lungs and organize around the infected macrophages, forming a granuloma, the hallmark structure of TB. The granuloma serves to contain the infection by “walling off” the bacteria within a tight structure of macrophages (including specialized foamy macrophages) and T-cells. In this phase, the infection may become latent, with the host remaining asymptomatic.
5. Caseation and Structural Changes: Over time, the center of the granuloma can undergo necrosis, leading to the development of a cheese-like material known as caseum. This occurs as foamy macrophages, rich in lipids, die and release their contents. Caseation compromises the structural integrity of the granuloma and creates an environment that favors bacterial persistence. M. tuberculosis further manipulates host lipid metabolism to promote the formation of foamy macrophages, supporting its long-term survival in a dormant or slow-replicating state.
6. Reactivation and Disease Progression: In healthy individuals, the granuloma can successfully contain the infection for years. However, if the immune system becomes weakened due to factors like HIV infection, malnutrition, diabetes, chemotherapy or other immunosuppressive conditions, the contained bacilli may reactivate. The caseous material liquefies, the granuloma collapses and bacteria are released into the airways. As the bacterial load rises, active pulmonary TB develops, characterized by symptoms such as persistent cough, fever, night sweats, chest pain and significant weight loss.
7. Cavitation and Transmission: During advanced disease, the softening of the caseous core leads to cavitation, hollow spaces in lung tissue where bacteria flourish and replicate rapidly. The bacilli are then expelled into the airways, making the patient highly infectious. When they cough or sneeze, they release new aerosolized droplets laden with M. tuberculosis, thus restarting the transmission cycle.
8. Dissemination Beyond the Lungs: If unchecked, M. tuberculosis can enter the bloodstream or lymphatic system, disseminating to other organs like the kidneys, brain and bones, leading to extrapulmonary TB. This systemic spread is often life-threatening and marks a severe stage of the disease.
Signs and Symptoms of Tuberculosis (TB)
|
Type |
Signs and Symptoms |
|
Latent TB |
◦ No symptoms |
|
Active Pulmonary TB |
◦ Persistent cough > 3 weeks |
|
Extrapulmonary TB |
Organ Involved |
|
Special Populations |
◦ Children: Growth failure, poor weight gain ◦ Atypical symptoms, widespread (disseminated) TB |
|
Less Common Symptoms |
◦ Asthenia (severe fatigue) |
Complications of Tuberculosis (TB)
Tuberculosis can lead to a wide range of complications affecting multiple organ systems especially if left untreated or in severe cases.15,16,17,18,19
1. Pulmonary Complications
a. Parenchymal Lesions:
◦ Open negative syndrome (Thin-walled cavities)
◦ Aspergilloma (fungal colonization in cavities)
◦ End-stage lung destruction leading to severely impaired respiratory function.
◦ Scar carcinoma (lung cancer arising in fibrotic lesions)
b. Airway Lesions:
◦ Tuberculous laryngitis (inflammation of the larynx)
◦ Bronchiectasis (permanent airway dilation)
◦ Tracheobronchial stenosis (narrowing of trachea/bronchi)
◦ Anthracofibrosis (fibrosis with black pigmentation)
◦ Broncholithiasis (calcified lymph nodes eroding into bronchi)
c. Vascular Lesions:
◦ Rasmussen aneurysm (aneurysm of pulmonary artery)
d. Pleural Lesions:
◦ Dry pleurisy (inflammation of the pleura without fluid accumulation)
◦ Pleural effusion (fluid in pleural space)
◦ Empyema (pus in pleural space) and bronchopleural fistula
◦ Pneumothorax (air in pleural cavity)
e. General Respiratory Complications:
◦ Cor pulmonale (right heart failure due to lung disease)
◦ Secondary amyloidosis (organ dysfunction due to amyloid deposits)
◦ Chronic respiratory failure
2. Hematologic Complications
a. Anemia in TB:
◦ Anemia of chronic disease
◦ Metabolic deficiencies (iron, folate, vitamin B12)
◦ Autoimmune hemolytic anemia
◦ Marrow infiltration/failure leading to reduced blood cell production.
b. Granulocyte Changes:
◦ Neutrophilia (increased neutrophils) common during active TB
◦ Neutropenia due to marrow suppression, nutritional deficiencies
◦ Leukemoid reactions (severe reactive leukocytosis)
c. Monocyte/Macrophage Abnormalities:
◦ Monocytosis (increased monocytes)
◦ Granuloma formation
◦ Risk of Hemophagocytic Syndrome (HPS)
d. Platelet Disorders:
◦ Thrombocytosis (high platelets)
◦ Thrombocytopenia due to disseminated intravascular coagulation (DIC), bone marrow infiltration and drug side effects
◦ Immune thrombocytopenic purpura (an autoimmune destruction of platelets)
e. Lymphocyte Changes:
◦ T-lymphocytopenia and reduced CD4/CD8 ratio
◦ Severe T-cell depletion seen even in HIV-negative TB patients
3. Coagulation Disorders
a. Hypercoagulable state
◦ Increased risk of thromboembolism (DVT, PE)
◦ Disseminated intravascular coagulation
◦ Thrombotic thrombocytopenic purpura
b. Hypocoagulable states also reported
c. Vascular endothelial injury due to cytokine release from activated monocytes, contributing to coagulation abnormalities.
4. Effects of Anti-TB Drugs on Blood and Hematologic System
a. Isoniazid: Anemia (pure red cell aplasia, sideroblastic anemia), thrombocytopenia, lupus-like syndrome
b. Rifampin: Thrombocytopenia, TTP, immune-mediated platelet destruction
c. Ethambutol: Rare autoimmune hemolytic anemia
d. PAS (para-aminosalicylic acid): Hemolytic anemia, neutropenia
e. Rifapentine: Neutropenia, lymphopenia
f. Linezolid: Myelosuppression causing anemia and thrombocytopenia
5. Severe Pulmonary and Extrapulmonary Complications
a. Severe Pulmonary TB:
◦ Acute respiratory distress syndrome (ARDS)
◦ Life-threatening hemoptysis (bleeding from lungs)
◦ Pneumothorax
b. Disseminated TB:
◦ Multi-organ involvement (most severe form)
◦ Meningitis (leading to coma, long-term neurological damage)
◦ Abdominal TB (intestinal obstruction/perforation)
c. Other Organ Involvement:
◦ Spinal TB: Back pain, stiffness
◦ Tuberculous Arthritis: Especially affecting hips and knees
◦ Liver/Kidney TB: Impaired waste removal and metabolism
◦ Cardiac TB: Rare, but may cause cardiac tamponade (life-threatening)
Conclusion
Tuberculosis continues to be a significant global health threat, despite being preventable and curable. Its persistence is driven by factors such as delayed diagnosis, the emergence of drug-resistant strains and widespread healthcare inequalities. A deep understanding of its causes, symptoms, risk factors and complications is crucial for effective control and prevention. To move toward a TB-free future, global efforts must focus on improving early detection, expanding access to care, promoting public education and advancing research into better therapies and vaccines.
In our next article, we will take a closer look at how tuberculosis is diagnosed and the latest approaches to its treatment, offering a complete guide from detection to recovery. Stay tuned!
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