Tuberculosis

• An Important Global Disease: Tuberculosis is a significant infectious disease on a global scale.
• Prevalence: Approximately 30% of the world's population carries the organisms responsible for tuberculosis.
• Annual Incidence: Every year, 8 to 10 million individuals develop tuberculosis.
• Affected Children: Of those cases, 1 million (10%) occur in children under the age of 15.
• Mortality: Annually, around 3 million individuals die from tuberculosis, including 250,000 children (6 per minute, 500 per day).
• Disproportionate Impact: Developing countries bear the greatest burden of tuberculosis cases.
• Most Cases Asymptomatic: The majority of children infected with tuberculosis do not exhibit clinical symptoms.
• Progression Risk: The lifetime risk of progression to active disease is 5-10 times higher in older children.
• Higher Risk in Early Years: Children under 2 years of age have an increased risk of progression to disease and extra-pulmonary tuberculosis (sometimes up to 40%).
• Smear-Negative Cases: In children under 12 years, 95% of tuberculosis cases are smear-negative, which can lead to underestimation of the disease burden.
• Reporting Challenges: The focus on smear-positive cases may result in the underreporting of tuberculosis cases in children.

Causes of Resurgence in Incidence of TB

• Worsening Economic Situations: Global resurgence of TB in the past two decades has been attributed to worsening economic conditions.
• Multidrug Resistance: The emergence of multidrug-resistant strains of tuberculosis has contributed to the resurgence.
• HIV Pandemic: The HIV pandemic has played a significant role in the resurgence of tuberculosis, as HIV weakens the immune system and increases susceptibility to TB infection.
• Decline in National Tuberculosis Control Programs: A decline in national tuberculosis control programs, possibly due to decreased funding or other factors, has also been implicated in the resurgence.
• Displaced Persons and Conflicts: The presence of a large number of displaced individuals living in poor conditions due to conflicts and wars has created environments conducive to the spread of tuberculosis.

• Mycobacterium tuberculosis
• Mycobacterium bovis
• Mycobacterium africanus
• Mycobacterium microfti

These are part of the TB species complex. Other environmental organisms responsible for opportunistic infections, especially in immunosuppressed individuals, include Mycobacterium Avian Complex (MAC).

Microbiology

The term Mycobacterium refers to bacteria that are fungus-like and often exhibit branching filamentous growth patterns. The discovery of the first mycobacteria, M. leprae, was made by Hansen in 1868. Robert Koch identified M. tuberculosis in 1882.

Characteristics of Mycobacteria

• Gram-resistant, non-motile, non-sporulating pleomorphic rods
• Unique cell wall composition containing peptidoglycan and complex lipids (mycolic acids)
• Cell wall resists decolorization by acids and alcohol after staining, classified as acid-fast bacilli (AFB)
• Cell wall is resistant to destruction by antimicrobial drugs, acids, alkali, boiling, UV, sunlight, and remains viable in sputum and droplet nuclei
• Virulent even in the dark
• Slow multiplication rate (approximately 16 hours)
• Antigenic properties:
• Protein antigens: Tuberculin protein elicits tuberculin sensitivity and antibody formation
• Lipids bound to proteins and polysaccharides:
• Muramyl dipeptide + mycolic acid induce granuloma formation
• Phospholipids induce caseous necrosis
• Cord factor inhibits leucocyte migration
• Polysaccharides induce antibody formation
• Lipoarabinomannan inhibits macrophage activation by IFN gamma
• Subvert macrophage killing, contributing to virulence

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• Increased risk of TB infections in:
• Household contacts of newly diagnosed smear-positive cases of TB
• Overcrowded and poor living conditions
• Very young age (< 5 years), adolescents (5 – 14 favored age)
• Severe malnutrition (vitamin deficiency)
• Children with recent measles, varicella, and pertussis infections
• HIV infection

• HIV infection increases the risk of TB by a factor of 20
• Increased risk of TB among HIV-positive children is partly attributable to immunosuppression and increased exposure to TB within the family.
• About 25% of HIV-positive children will develop TB each year.
• Mortality in co-infection is 6 times that of TB infection alone
• More rapid HIV progression
• TB manifestations are more severe in HIV-positive children, with lower cure rates and higher mortality.
• Higher rates of drug-resistant TB
• Anti-TB treatment is less efficacious if not given in conjunction with ARVs
• HIV-positive children are at risk of diagnosis errors as well as delayed diagnosis of TB
• Timing of TB infection:
• In adults, latent infection often acquired before HIV infection, and subsequent disease may represent a reactivation of a remote infection
• In contrast, most children are infected with HIV perinatally and are only exposed to and infected with TB at a later point in time

Source of Infections:

• Most important source is sputum of persons with open tuberculosis
• Unpasteurized milk

Mode of Spread:

• Inhalation
• Ingestion
• Penetration of skin and mucous membrane
• Genital and placental transmissions

Tuberculosis is a chronic inflammatory disease characterized by prolonged inflammation, tissue destruction, and attempts at repair occurring simultaneously.

The immune response to the tubercle bacilli, which have low toxicity, is called a delayed hypersensitivity reaction.

Granulomatous inflammation, a specific type of chronic inflammation, is a hallmark of TB. A focal area of granulomatous inflammation is termed a granuloma. In tuberculosis, the granuloma is referred to as a tubercle.

Key characteristics of the tubercle include:

• A central area of caseous necrosis, which is a type of tissue death characterized by a soft and cheese-like appearance.

This complex interplay of inflammation, immune response, and tissue damage contributes to the pathophysiology of tuberculosis.

Potential Outcomes of Tuberculosis

Tuberculosis can result in various outcomes depending on the interplay between the immune response and the bacteria. The potential outcomes include:

• Containment: In some cases, the immune response effectively contains the infection, preventing the development of active disease.
• Primary Parenchymal Disease: This refers to the initial infection causing disease in the lung tissue.
• Progressive Primary Disease: In some cases, the primary infection may continue to progress despite an ongoing immune response.
• Reactivation Disease: After a period of latency, the infection can reactivate and cause disease, often in a more severe form.

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Primary parenchymal disease is the most common manifestation of tuberculosis.

Primary Infection and Primary Complex

Primary Focus:

• Size: The size of the primary focus varies, ranging from a few millimeters to 2 centimeters in diameter.
• Site: The primary focus is usually situated in the sub-pleural region of the lung.
• Symptoms & Signs: The primary focus may present in various ways:
• It may be symptomless.
• It may be associated with minor symptoms such as malaise and anorexia.
• It may be associated with muco-cutaneous manifestations like erythema nodosum and phlyctenular conjunctivitis.
• Some individuals may develop Poncet's arthritis.

Primary Complex:

The primary complex consists of the primary focus and the regional lymph nodes. It can have two possible outcomes:

1. Successful Containment: The primary complex can be effectively contained by the host's immune system.
2. Progression to Active Disease: Alternatively, the primary complex can progress to active tuberculosis. The risk of progression is about 15% in the first 10 years after infection.

Progression of Primary Infection to Active Disease

1. Tuberculous Pneumonia: The primary focus can spread to contiguous parts of the lungs, leading to tuberculous pneumonia.
2. Consolidation: The primary focus and regional lymph nodes may merge, giving rise to an area of consolidation.
3. Cavity Formation: Extensive caseation and liquefaction can develop, resulting in cavity formation.
4. Atelectasis and Emphysema: Inflamed nodes may compress neighboring bronchi, leading to atelectasis or emphysema.
5. Endobronchial Tuberculosis: Nodes may erode through the bronchial wall, causing endobronchial tuberculosis.
6. Bronchogenic Dissemination: Tubercle bacilli may be discharged into the bronchial lumen, leading to bronchogenic dissemination to other lung areas.
7. Haematogenous Spread: Nodes may erode into blood vessels, resulting in hematogenous spread to other organ systems.
8. Fibrosis and Encapsulation: The affected nodes may develop fibrosis and encapsulation, with viable tubercle bacilli persisting within the node for many years. This may serve as the source of reactivation tuberculosis.

Wallgreen Time Table 1948

• MANIFESTATION OF PRIMARY INFECTION (3 – 8 WEEKS)
  • Fever of onset – last 3 – 4 weeks of incubation period
  • Hypersensitivity phenomena
    • Phlyctenular keratoconjunctivitis
    • Erythema nodosum
    • Poncet’s arthritis
• EARLY COMPLICATIONS OF BACILLAEMIA (3 MONTHS - 2 YEARS)
  • Pulmonary tuberculosis – within a few months of primary infection
  • Miliary and meningeal tuberculosis – 2-6 months
  • TB adenitis – 3-9 months
  • Bones and joints – several years
  • Renal and genital tuberculosis – may take over a decade
  • Pulmonary lesions occurring as a result of reactivation of a dormant tuberculosis focus previously established in the body takes a number of years after primary infection
• COMPLICATIONS OF PRIMARY FOCUS (1 YEAR)
  • Pleural effusion
  • Cavitation/coin lesions
• COMPLICATIONS OF REGIONAL LYMPH NODES (3-9 MONTHS)
  • Bronchial compression + hyperinflation/atelectasis
  • Bronchial erosion + collapse consolidation (segmental)
• LATE COMPLICATIONS OF BACILLAEMIA
  • Bone and Joints (within 3 years)
• MODERATELY LATE COMPLICATIONS OF PRIMARY COMPLEX (5 YEARS)
  • Progressive pulmonary disease
• VERY LATE COMPLICATIONS
  • Usually >5 years

• Probable TB
  • Known contact with TB case and/or positive Tuberculin Skin Test (TST)
  • AND Suspicious symptoms and suggestive Chest X-ray (CXR)
  • OR Extra-thoracic TB manifestations
• Confirmed TB
  • Bacteriologic confirmation
    • Sputum smear
    • Sputum or gastric aspirate culture
    • Confirmation from other specimen
  • Presumptive TB – Clinical history and contact

• Anatomical site – Pulmonary TB (PTB) / Extra-pulmonary TB (EPTB)
• Bacteriological results
  1. Bacteriological positive/negative TB case;
  2. Smear positive PTB/smear negative PTB
• History of previous treatment
  1. New patient – no drugs or for less than 4 weeks
  2. Previously treated/retreatment patient – received 4 weeks or more of anti-TB treatment in the past
• Based on treatment outcome as
  1. Relapse: Previously had outcome of cured or treatment completed but now positive
  2. Bacteriologically or clinically diagnosed
  3. Treatment failure: Previously treated TB patient who remains or became positive at 5 months or more of treatment
• Based on HIV status
  • HIV positive/negative/status unknown

Pulmonary Tuberculosis

Commonest form of tuberculosis occurring alone or in combination with other forms in 70% of cases. Pulmonary tuberculosis in children consists mainly of primary complex and direct progression of its component.

Clinical Features

Early symptoms are usually vague:

• Chronic cough > 21 days
• Fever > 38°C for more than 14 days after excluding common causes of fever, such as malaria or pneumonia
• Anorexia
• Weight loss or
• Failure to thrive
• Haemoptysis

Signs:

• Dyspnoea
• Tachypnoea
• Localized wheezing
• Decreased breath sounds
• Crepitations
• Bronchial breath sounds
• Chest examination may reveal no abnormality
• Clinical features of reactivation TB in older children are similar to those of the primary infection, but cough is usually productive and there may be chest pain

Diagnosis

History

When taking a history from a patient with suspected tuberculosis, it's important to gather detailed information that can help in accurate diagnosis and management. Here are the key aspects to consider:

• Detailed history of current illness: Explore the patient's presenting symptoms in detail. Inquire about any cough, its duration (chronic cough > 21 days), frequency, and any changes in the type of cough (productive or dry).
• Past medical history: Ask about any past medical conditions, hospitalizations, surgeries, or chronic illnesses. Previous episodes of tuberculosis, if any, should be noted.
• Family and social history: Investigate whether any family members or close contacts have had tuberculosis. Inquire about the patient's living conditions, exposure to crowded places, and any travel to areas with a high prevalence of tuberculosis.
• History of contact: Determine if the patient has been in close contact with individuals known to have tuberculosis. This could include family members, friends, or colleagues.

Additionally, inquire about the presence of other symptoms that may be associated with tuberculosis, such as:

• Fever (> 38°C) for more than 14 days after excluding common causes of fever, such as malaria or pneumonia.
• Anorexia (loss of appetite) and weight loss.
• Failure to thrive in children, indicating poor growth and development.
• Haemoptysis (coughing up blood), which can be a worrisome symptom and requires immediate attention.
• Chest pain, particularly in cases of reactivation tuberculosis in older children.

Here is an overview of important questtions to ask:

• Cough Characteristics:
  • Ask about the nature of the cough (dry or productive).
  • Inquire about the color and consistency of sputum, if present.
  • Ask if the cough is worse at certain times of the day or during specific activities.
• Fever and Night Sweats:
  • Explore the presence of fever, including its pattern (continuous or intermittent).
  • Ask about night sweats, particularly if they are drenching and disturb sleep.
• Respiratory Symptoms:
  • Inquire about shortness of breath, rapid breathing, or difficulty breathing.
  • Ask if the patient experiences wheezing or chest tightness.
• General Symptoms:
  • Ask about fatigue, weakness, and overall feeling of illness.
• Other Associated Symptoms:
  • Investigate any joint pains, bone pains, or muscle pains.
  • Inquire about headaches, confusion, or neurological symptoms.
• Systemic Symptoms:
  • Explore any loss of appetite, unintentional weight loss, or fatigue.
• Exposure to Tuberculosis:
  • Ask if the patient has been in close contact with individuals known to have tuberculosis or chronic cough.
  • Inquire about exposure to crowded or enclosed spaces where tuberculosis transmission could occur.
• Medical History:
  • Explore the patient's medical history, including any chronic illnesses (e.g., diabetes, HIV).
  • Inquire about past tuberculosis episodes, if applicable.
• Travel History:
  • Ask if the patient has traveled to areas with a high prevalence of tuberculosis.
• Immunization History:
  • Inquire about BCG (Bacillus Calmette-Guérin) vaccination status.
• Medication History:
  • Ask about any medications the patient is currently taking, including antibiotics.
• Social History:
  • Inquire about the patient's occupation, lifestyle, and habits (e.g., smoking, alcohol consumption).
• Allergies:
  • Ask if the patient has any known allergies to medications.

Investigations

1. Tuberculin skin test: A positive result indicates exposure to tuberculosis, but further tests are needed for diagnosis.
2. Chest radiograph: May show characteristic changes like upper lobe infiltrates or cavitations.
3. Bacteriological investigations:
   • Sputum staining: Acid-fast bacilli (AFB) may be visible under microscopy.
   • Gastric washings staining and culture: AFB presence and growth in culture indicate tuberculosis.
   • Broncho-alveolar lavage: Used for obtaining samples for culture and AFB detection.
4. ESR (Erythrocyte Sedimentation Rate): Elevated ESR suggests ongoing inflammation or infection.
5. FBC (Full Blood Count): May reveal anemia and other changes associated with infection.

Newer Methods of Diagnosing TB

1. LAM:
   • Antigen capture ELISA assays for lipoarabinomannan detection in sputum and urine.
   • Rapid results within 2-3 hours.
   • 76.5% sensitive in smear-negative cases, 80.3% sensitive overall, 99% specific.
2. Interferon Gamma Release Assays (IGRA) – Quantiferon, T-Spot
3. BACTEC:
   • Offers slightly superior sensitivity and reduced turnaround time compared to conventional LJ.
4. MODS (Microscopic observation drug susceptibility assay)
5. GeneXpert MTB/Rif:
   • Based on PCR technology.
   • Detects TB and rifampicin resistance in less than 2 hours.
   • Used in various clinical scenarios, including known contacts of confirmed DR-TB cases, children with TB symptoms, and retreatment cases.
6. Line Probe Assay (LPA):
   • Rapid diagnosis of drug-resistant TB on positive specimens.
   • Can detect MTB and resistance to Rif and INH from one specimen.
   • Reduces MDR-TB diagnosis time to 7 days.
   • Specific for MTB complex but has limitations like not distinguishing live from dead bacteria and labor-intensive process.

Tuberculin Skin Testing (TST)

Mantoux Test:

• TST is used to detect contact with TB bacilli.
• Most commonly used methods are Heaf and Mantoux test.
• Mantoux test is more clinically useful.

Other Methods:

• Heaf: 6-pronged gun.
• Rosenthal/Tine: 4 meta prongs.
• Mono-vacc: 9-point scarifier.
• Applitest.
• Sclavo PPD.

Mantoux Test Details:

• Antigen used: PPD containing 5 tuberculin units.
• Administered intradermally.
• Test is read as millimeters of induration at 48 to 72 hours.
• Positive test indicates M. tb infection but not necessarily disease.
• Interpretation:
• 0 – 4mm = negative.
• 5 – 9mm = borderline.
• ≥ 5mm = positive in HIV-infected and severely malnourished children.
• ≥ 10mm = positive in all other children, regardless of BCG vaccination.

False Negative	False Positive
Faulty technique Pre-allergic phase Immunosuppression: Overwhelming disease Malnutrition Steroids Cytotoxic drugs	BCG vaccination Atypical Mycobacterium Hypersensitivity to non-tuberculo-prot component

Uses of TST

• Assessing the prevalence of TB in communities
• Evaluating the effectiveness of TB control measures
• Determining the prevalence of opportunistic infections
• Assisting in differential diagnosis of TB
• Identifying individuals requiring BCG vaccination or prophylaxis

Chest Radiograph

There are no pathognomonic radiological signs of tuberculosis.

However, certain radiological lesions may suggest tuberculosis:

• Hilar adenopathy
• Widened mediastinum due to enlarged lymph nodes
• Parenchymal lesions:
  • Patchy infiltrates
  • Consolidations
  • Atelectasis
  • Pleural effusion
  • Cavities

Rarely, a chest X-ray may appear normal.

Bacteriological Diagnosis in Children

Isolation of TB bacilli from clinical specimens remains the gold standard for diagnosis.

However, isolating the organism in children is more challenging due to paucibacillary disease.

The yield of the organism is low, even in the best centers (<50%).

Specimen Collection

1. Sputum:
   • Children 10 years or older who can expectorate and produce sputum.
   • Collect 2 specimens (on-spot day 1; day 2 – early morning).
   • Consider induced sputum collection.
2. Gastric Aspiration (fasting, early morning):
   • Perform aspiration of gastric contents while fasting, ideally while still recumbent after overnight sleep.
   • Usually performed in hospitalized patients.
   • Collect specimens on three consecutive days.
   • Strictly adhere to recommended collection techniques to improve yield.

Interpretation of Smear Microscopy Results:

• Positive AFB: At least one tubercle bacillus on one or more sputum smears.
• Negative AFB: Both smears show no AFB.
• Scanty: Refers to 1 – 9 AFB/100 oil immersion of ZN stain or <1 AFB per field for auramine staining.

Note:

• Smear microscopy – 10,000 TB bacilli/ml of sputum = positive.
• GeneXpert – 130 bacilli/ml of sputum = positive.
• Culture – 10-100 bacilli/ml.
• Culture – Lowenstein Jensen (3-6 weeks + 4 weeks).
• Middlebrook culture.
• Automated Bactec 460 (1-3 weeks; 3–5 days).

Differential Diagnosis

• Pneumonia: Infections like bacterial, viral, and mycoplasma can present with similar respiratory symptoms.
• Lung Abscess: May cause symptoms such as cough, fever, and chest pain, similar to pulmonary tuberculosis.
• Bronchiectasis: Chronic condition characterized by damaged airways and recurrent respiratory infections, leading to similar symptoms.
• Pulmonary Fungal Infections: Fungal infections can mimic tuberculosis with respiratory symptoms and radiological findings.
• Pulmonary Neoplasm: Lung tumors can cause cough, chest pain, and other respiratory symptoms, overlapping with tuberculosis.

Pleural Effusion

TB pleural effusion can occur due to various mechanisms:

• Subpleural primary focus ruptures into the pleural cavity.
• Caseous node ruptures into the pleural cavity.
• Haematogenous spread.
• Allergic response to tuberculo protein.

Clinical Features

Symptoms:

• Fever
• Weight loss
• Chest pain on deep inspiration

Signs:

• Dullness to percussion
• Diminished or absent breath sounds

Pleural Fluid:

• Sero-Fibrinous, sometimes blood-stained
• Protein 2-4 g/dL
• High white cell count with predominance of lymphocytes
• Culture yields tubercle bacilli in less than 20% of cases

Miliary Tuberculosis

Miliary tuberculosis is the most severe form of disseminated TB.

Clinical Manifestations

Manifestations can vary based on factors such as the organism load, affected organs, and the child's immune status. Symptoms may have an explosive or insidious onset.

Symptoms:

• Fever
• Anorexia
• Weight loss
• Cough
• Wheezing

Signs:

• Generalised lymphadenopathy
• Hepatomegaly
• Splenomegaly
• Respiratory distress
• Signs of meningitis or peritonitis present in 20-40% of cases
• Choroidal tubercles

Investigations

• Tuberculin skin test
• Chest X-ray (CXR)
• Cerebrospinal fluid (CSF) tap
• Histological examination of:

• Lymph nodes
• Liver biopsy
• Marrow biopsy

Differential Diagnosis of Miliary Picture on CXR

When encountering a miliary pattern on chest X-ray (CXR), consider the following differential diagnoses:

• Sarcoidosis
• Eosinophilic pneumonia
• Pulmonary fungal infection
• Chicken pox pneumonia
• Childhood histiocytosis syndrome
• Lymphoid interstitial pneumonitis (LIP)

Tuberculosis of the CNS

Tuberculosis of the central nervous system (CNS) includes:

• Tuberculous meningitis
• Tuberculoma

Tuberculous meningitis

Tuberculous meningitis is characterized by its occurrence about 2 to 6 months after the primary infection. It is most common in children aged 6 months to 4 years and arises due to the hematogenous spread of tubercle bacilli to the cerebral cortex and meninges.

Clinical Manifestation:

It can be divided into three stages:

• Stage I: Non-specific symptoms like fever, headache, weight loss, irritability, and drowsiness.
• Stage II: Lethargy, nuchal rigidity, seizures, positive Kernig’s sign, vomiting, signs of brainstem involvement, cranial nerve palsies, and possibly other focal neurological signs.
• Stage III: Hemiplegia or paraplegia, coma, decreasebrate rigidity, opisthotonus. Fundoscopy may show papilloedema and choroidal tubercles.

Investigations

1. Tuberculin skin test
2. CXR
3. Examination of CSF

CSF Picture

The CSF findings may include:

• Appearance: May be straw-colored or clear and colorless.
• White Blood Cells (WBC): 10-500 cells/cmm with predominance of lymphocytes.
• Protein: Protein levels may be over 1 g/dl.
• Glucose: Glucose levels are low, typically less than 40 mg/dl.
• Spider Web Appearance: Visible after 30 minutes.
• Staining: ZN stain may yield Acid-Fast Bacilli (AFB).
• Culture: Culture may be positive.

Prognosis

The prognosis of tuberculous meningitis depends on the stage of the disease at the commencement of therapy:

• Stage I: Prognosis is good.
• Stage III: Mortality is high, and a high percentage of those who survive have complications such as blindness, deafness, paraplegia, mental retardation, speech disturbance, cranial nerve palsies, and hydrocephalus.

Tuberculoma

Tuberculoma

Presents as an intracranial space-occupying lesion, usually infratentorial, and may be single or multiple.

Clinical Manifestation

• Headache
• Fever
• Convulsions
• Lateralizing signs

Investigations

1. Tuberculin skin test
2. Skull X-ray
3. CXR
4. CT Scan of the brain shows discrete masses with surrounding edema

Diagnosis is often made at surgical exploration for intracranial tumor.

Tuberculosis of Superficial Lymph Nodes

Occurs within 3 – 9 months of primary infection and can affect any group of nodes. Glands are usually discrete, mobile, firm, and non-tender but may become matted together if there is periadenitis. May form a discharging sinus. There may or may not be associated constitutional symptoms.

Investigations

1. Tuberculin skin test
2. CXR
3. Fine needle aspiration biopsy or excision of nodes for histological exam

Differential Diagnosis

• Pyogenic lymphadenitis
• Hodgkin's lymphoma
• Acute lymphocytic leukemia
• Fungal infection of lymph nodes
• Infection with atypical mycobacteria
• HIV/AIDS

Tuberculosis of the Spine

The vertebrae are the commonest and most important bones affected by tuberculosis in children.

May arise by:

• Lymphatic spread from an adjacent area
• Hematogenous spread from a primary focus

Clinical Features

• Pain in the back
• Spinal rigidity and limitation of spinal movement
• Kyphosis
• Scoliosis with or without gibbus
• Increased muscle tone
• Decreased muscle power which may progress to paralysis

There may be quadriplegia if the cervical vertebrae are affected or paraplegia if the other vertebrae are affected.

There may be loss of voluntary bladder control.

Investigations

• Tuberculin skin test
• CXR
• Radiograph of the affected part of the vertebral column

Complications

• Paraspinal abscess
• Psoas abscess
• Retropharyngeal abscess

Differential Diagnosis

1. Idiopathic scoliosis or kyphosis
2. Acute non-tuberculous osteomyelitis of the spine
3. Rickets
4. Secondary malignancies affecting the CNS e.g. Burkitt’s lymphoma
5. Histoplasmosis Duboisii of the spine

If sputum available:

• Collect 2 sputum specimens for AFB microscopy
• Collect 1 sputum specimen for Xpert MTB/Rif
• Perform HIV test

If sputum unavailable:

• Collect one clinical specimen for GeneXpert MTB/Rif
• Perform HIV test

Main objectives in TB Treatment:

• To rapidly kill most bacilli in order to:
  • Stop disease progression
  • Prevent transmission of infection
• To effect cure and prevent relapse (eliminate dormant bacilli)
• To do the above with minimal adverse reactions
• To prevent the development of drug-resistant organisms

Desirable Characteristics of Drugs:

• Bactericidal
• Good sterilizing activity
• Prevention of drug resistance
• Low toxicity

Other Basic Principles:

• Combination therapy always
• Use fixed dose combination drugs if possible
• DOTS – directly observed therapy, short course
• Uninterrupted drug supply

DOT:

• Right drug at the right time at the right dose
• Patient-centered with proper communication between the patient and treatment supporter
• Promotes patient education, adherence, early identification of challenges with treatment
• Educate on cough etiquette, treatment duration, number of daily tablets, interval for sputum follow-up examination, and side effects

Anti-TB Treatment: 2 Phases

• Intensive phase
  • To rapidly eliminate the majority of bacilli
  • To prevent the emergence of drug resistance
• Continuation phase
  • To eradicate dormant organisms
• Either phase can be given daily

To improve compliance, directly observed therapy short course (DOTS) is desirable at least during the intensive phase.

1st Line Anti-TB Drugs

1. Rifampicin
2. Pyrazinamide
3. Isoniazid
4. Ethambutol

Isoniazid

• High early bactericidal activity (EBA)
• Good pharmacokinetics
• Low toxicity
• Moderate sterilizing activity

Rifampicin

• Moderate EBA
• Excellent sterilizing activity
• Considerable enzyme induction
• Modern short-course regimens are totally dependent upon rifampicin

Doses of First-line Anti-TB Drugs

There is now increasing evidence that children, especially younger children, need higher doses of antituberculosis agents to reach serum concentrations equivalent to those of adults receiving the same dose – this is why WHO is in the process of recommending higher doses of 1st-line drugs in children.

Codes for TB Treatment Regimens

• 2SHRZ/4H3R3
• Number in front of each phase = duration in months
• Letters = abbreviation for the drugs
• Subscript numbers following a letter = number of doses per week of that drug.
• If no subscript = drug is daily

Revised Treatment Guideline for Childhood TB (2013)

Note:

• Streptomycin no longer recommended for new patients
• Intermittent regimens not recommended in HIV-endemic setting

Treatment NTBLCP (Nigeria)

Regimen 1: (2 RHZE/4RH) for new cases
All children with all forms of TB with the exception of TB meningitis and osteo-articular TB

Regimen 2: (2 RHZE/10RH) for TB meningitis and osteo-articular TB

First-line Anti-TB Drugs: Adverse Effects

Adjunct Therapy

• PYRIDOXINE – 25mg daily until treatment is completed
• Steroids – oral prednisolone 1-2mg/kg/day for 3 weeks then taper over 3-4 weeks (reduce by 25% per week)

Indication for Corticosteroid

1. Large pleural effusion
2. Endobronchial tuberculosis
3. Pericardial effusion
4. Tuberculous meningitis
5. TB laryngitis
6. TB adrenal glands
7. TB renal tract
8. Severe hypersensitivity to antitb drugs

Supportive Therapy

• Improved Nutrition
• Screening of immediate family members
• Surgical intervention where necessary

2nd-line drugs – WHO Reserve Drugs

• Ethionamide/prothionamide
• Ofloxacin/levofloxacin/moxifloxacin
• Cycloserine/terizidone
• Kanamycin/amikacin
• Capreomycin
• Para-amino salicylic acid

Monitoring TB Treatment

Regularly monitor treatment progress and patient's well-being through the following measures:

• Liver Function Tests (LFTs) at the start of treatment, after 2 months, and upon completion.
• Clinical assessments, including weight measurements.
• Erythrocyte Sedimentation Rate (ESR) checked weekly and monthly.
• Keep track of drug intake using charts and monitor urine color.
• Conduct Acid-Fast Bacillus (AFB) microscopy at 2, 3, 5, and 6 months.

Dealing with Treatment Interruption + Positive Smear

If a patient interrupts treatment and is smear positive (indicating TB bacilli presence):

• Trace the patient to understand the situation.
• If interruption is <1 month:
  • No need for additional AFB testing.
  • Continue treatment and extend it to compensate for the missed time.
• If interruption is ≥ 2 months:
  • For negative smear or extrapulmonary TB (EPTB):
    • Decide whether to restart, continue, or not provide further treatment based on individual circumstances.
  • For ≥ 1 positive smear:
    • Use GeneXpert MTB/Rif to determine the appropriate treatment based on the result.

Handling Treatment Interruption + Inability to Produce Sputum

If a patient can't produce sputum and there's treatment interruption:

• If <2 weeks in the intensive phase:
  • Regardless of symptoms, continue treatment and extend it to cover the missed time.
• If >2 weeks in the intensive phase or >2 months in the continuation phase:
  • If asymptomatic, continue treatment and extend for the missed time.
  • If symptomatic, restart the regimen, which may be a six/nine-month regimen based on the specific case.

1. Case Finding and Effective Treatment.
2. Contact Tracing and INH Chemoprophylaxis.
3. BCG Vaccination.
4. Improvement in the General Standard of Living.

Contact Tracing

• Contact any person exposed to an index case.
• Household Contacts:
• Household contacts refer to individuals who have shared the same enclosed living space for at least eight continuous hours or for frequent prolonged periods with the index case during the three months before the commencement of the current treatment episode.
• All children with symptoms suggestive of tuberculosis.
• All children aged less than 6 years who are close contacts of infectious tuberculosis cases.
• All children with known or suspected immunocompromise.
• All children contacts of MDR/XDR tuberculosis.
• Children who are contacts of smear-positive tuberculosis cases should undergo clinical investigations.
• Screen with Tuberculin Skin Test (TST) and Chest X-Ray (CXR).

If the mother is diagnosed with tuberculosis during the third trimester of pregnancy or shortly after delivery:

• The mother's treatment should be started or continued if it has already begun.

If the baby is healthy:

• The baby should begin taking Isoniazid (INH) shortly after birth and continue for 6 months.
• The baby can receive the Bacillus Calmette-Guérin (BCG) vaccine 2 weeks after birth.

If the baby is not well:

• Evaluation for tuberculosis is necessary.

Types of Drug Resistance

• Primary resistance: No previous anti-TB treatment or treatment lasting less than 1 month.
• Acquired or secondary resistance: Previous anti-TB treatment lasting more than 1 month.

Classification of Drug Resistance

• Mono-drug resistance: Resistance to a single drug.
• Poly-drug resistance: Resistance to 2 or more drugs, excluding both INH and RMP.
• Multi-drug resistant (MDR TB): Resistance to INH and RMP, possibly other drugs.
• Extensively drug resistant (XDR-TB): Resistance to INH and Rifampicin, and at least three of six main classes of Second Line anti-TB drugs (e.g., aminoglycosides, fluoroquinolones, cycloserine, etc.).
• PAN-RESISTANT TB: Resistance to all anti-TB drugs.

Causes of Drug Resistant TB

• Poor management of drug-susceptible or mono-resistant TB cases, such as incorrect treatment regimens, interrupted treatment, and poor patient adherence.
• Poor management of MDR-TB cases leading to the transmission of MDR-TB strains. This includes late diagnosis, lack of drug susceptibility testing in relapse/retreatment cases, and inadequate infection control measures, especially in high HIV prevalence settings.

Risk Factors for Drug Resistant TB

• Failure of retreatment and chronic TB.
• Exposure to a known drug-resistant TB case.
• Failure of category 1 treatment.
• History of TB treatment outside the national programme.
• Children under 2 years are at higher risk, especially those with impaired immunity such as HIV infection and malnutrition.

Diagnosis of MDR-TB in Children

Clinical features and chest radiography cannot reliably distinguish between drug-sensitive (DS) and drug-resistant (DR/MDR) TB. DR TB is a microbiological diagnosis.

In children, the diagnosis of MDR-TB is often challenging due to the paucibacillary nature of TB:

• Confirmation of MDR-TB only occurs if an MDR M. tuberculosis strain is isolated from a child. Obtain specimens from all possible sources for culture and susceptibility testing.
• If a child has known contact with an adult MDR pulmonary TB case, it's probable that the child has MDR TB.

Suspect drug-resistant TB further if:

• A child deteriorates on treatment despite adherent therapy.
• An adult index case with an unknown susceptibility pattern is:
• A treatment failure (sputum smear positive after 5 months of treatment).
• A retreatment case.
• A chronic TB case (TB despite 2 previous treatment courses).

Management of MDR-TB in Children

• Confirm MDR-TB if possible.
• If MDR-TB is confirmed, also perform Drug Susceptibility Testing (DST) for 2nd-line drugs.
• Management takes place at a specialized MDR-TB clinic.
• Use 1st-line drugs to which the isolate is susceptible along with 2nd-line drugs.
• Be mindful of different drug groups and potential cross-resistance.
• 2nd-line drugs are generally more toxic than 1st-line drugs.
• Assessment of adverse events is more challenging in young children.

Drug-Resistant (DR) Tuberculosis Management

For DR Tuberculosis:

• Collect sputum sample for GeneXpert testing.
• If the result is TB positive but not rifampicin resistant, initiate Directly Observed Treatment Short Course (DOTS) regimen.
• If rifampicin resistance is detected, enroll the patient in DR-TB treatment.
• Send sputum for culture to determine Drug Susceptibility Testing (DST) for further management.

Standardized regimens for the country include:

• 8-month regimen: Kanamycin – Pyrazinamide – Cycloserine – Levofloxacin – Pyrazinamide
• 12-month regimen: Levofloxacin – Cycloserine – Pyrazinamide – Levofloxacin

Pyridoxine is added as supportive treatment.

Extensively Drug-Resistant (XDR) Tuberculosis

The treatment principles for XDR-TB are the same as for MDR-TB.

Second Line Anti-TB Drugs for Children

Tuberculosis (TB) and HIV infections are a dual pandemic in sub-Saharan Africa. The decline in immune function due to HIV leads to the reactivation of latent TB disease. TB is the most common cause of death among People Living With HIV/AIDS (PLWHA), contributing to 30-40% of HIV/AIDS-related deaths worldwide.

Screening for TB is crucial for every child confirmed to have HIV infection, as 20-60% of HIV-positive children are co-infected with TB. These children often live with HIV-positive adults, further increasing the risk of exposure.

Diagnosis can be challenging in cases of TB/HIV co-infection. HIV-positive patients are more likely to have smear-negative pulmonary TB or extrapulmonary TB. Interpretation of Mantoux tests for TB screening is considered positive if the induration is ≥ 5mm.

The introduction of Highly Active Antiretroviral Therapy (HAART) can lead to drug interactions and requires careful management. Immune Reconstitution Inflammatory Syndrome (IRIS) can also occur.

IRIS, or Immune Reconstitution Inflammatory Syndrome, is a paradoxical worsening of clinical symptoms or emergence of new inflammatory manifestations following the initiation of antiretroviral therapy (ART) in individuals co-infected with tuberculosis (TB) and HIV. It occurs due to the restoration of immune responses as ART suppresses HIV replication, leading to enhanced recognition and exaggerated immune reactions against previously subclinical TB infections. One of the ways it can be prevented is by screening for TB infection before starting ART. If active TB is present, initiate TB treatment first and ensure that it is well underway before beginning ART.

It's important to note the high incidence of Multidrug-Resistant TB (MDR TB) in HIV-infected individuals. Therefore, all HIV-infected children should undergo Gene Xpert testing to detect drug-resistant TB strains.