TUBERCULOSIS

Diagnosis In a child with symptoms of TB, the

following are adequate for diagnosis: +ve Tuberculin Skin Testing (TST) or Interferon

Gamma Release Assays (IGRA) Abnormal Chest X-Ray History of TB contact

Among TB cases → extrapulmonary manifestations are present in 15% of adults & 25-30% of children

• TST• IGRA• Chest X-Ray• Sputum examination• Pleural fluid examination• Pericardial fluid examination• Lymph node examination• CSF analysis• CT/MRI of brain• Bone biopsy• GI lesion examination• Urine examination

Tuberculin Skin Testing (TST)

Delayed type hypersensitivity reaction Intradermal injection of 0.1 ml of PPD (purified protein derivative) Lymphokines induce induration (local vasodilatation, edema, fibrin deposition & other inflammatory cells recruitment) Time : 48-72 hours Induration of ≥ 10 mm in a BCG vaccinated child or

adult → positive For high risk population, HIV infected persons or

immunosuppressed persons ≥ 5 mm is positive For low risk population ≥ 15 mm is positive

TST False positive results in:

Prior BCG vaccination Non tuberculous mycobacterial infections

(NTM) Other allergic or hypersensitivity reactions

False negative results in: Immunosuppression Live vaccines Corticosteroid therapy Malnutrition Sarcoidosis Hodgkin’s disease URTI

Induration ≥5 mm

Induration ≥10 mm Induration ≥15 mm

• Children in close contact with known or suspected contagious people with TB• Children suspected to have TB: • Chest X-Ray

findings with active or previous TB

• Clinical evidence of TB

• immunosuppressive therapy or conditions (including HIV)

• Children at increased risk of disseminated TB: • Children younger than 4

yrs of age• Children with other medical

conditions (Hodgkin’s, DM, chronic renal failure, malnutrition)

• Children with increased exposure to TB:• Born in high prevalence

regions• Exposed to adults who are

HIV infected, homeless, drug abusers, residents of nursing homes etc

• Travel to high prevalence regions

• children ≥4 yrs of age without any risk factor

POSITIVE TST RESULTS DEFINITIONS

Interferon Gamma Release Assays Detect Interferon gamma generation by

patient’s T cells in response to M. tuberculosis antigens

Two blood tests: T- SPOT TB: measures number of

lymphocytes producing interferon gamma Quanti FERON TB: measures whole blood

concentration of interferon gamma Advantage over TST is lack of cross

reaction with BCG vaccination & most other mycobacteria

Chest Radiograph Usual sequence is hilar lymphadenopathy,

focal hyperinflation & atelectasis Collapse-consolidation or segmental TB Occasionally calcification of primary focus or

regional lymph node Lobar pneumonia Cavity formation (liquefaction of lung

parenchyma in progressive disease can cause formation of thin walled cavity)

Bullous tuberculous lesions (rare) can cause pneumothorax

Miliary pattern

Hilar Lymphadenopathy

Hilar Lymphadenopathy Collapse-consolidation or

Segmental TB

Calcification

Cavity Formation

Pneumothorax

Miliary Pattern

Miliary Pattern

Sputum Examination Smear staining & culture in older

children Gastric aspirates (early morning) for 3

consecutive days in infants & younger children

Organism yield <50% of cases Culture yield from bronchoscopy is even

lower (+ve in case of endobronchial disease or fistula)

Pleural Fluid ExaminationNormal Tuberculosis

Colour Clear Yellow/straw coloured (maybe tinged with blood)

TLC None (or few) Several hundreds to several thousands / cubic mm.PMNs predominate early, lymphocytes predominate later

Protein 3 g/dL 2-4 g/dL

Glucose Parallel serum values

Low to normal (20-40 mg/dL)

Acid fast smear Negative Rarely positive

Culture Negative Positive in < 30% of cases

Biopsy of pleural membrane is more likely to yield a positive acid fast stain or culture

Granuloma formation can usually be demonstrated

Pericardial Fluid Analysis 0.5-4% of TB children have tuberculous

pericarditis Serofibrinous or hemorrhagic fluid Acid fast smear of fluid is rarely positive Culture +ve in 30-70% of cases Pericardial biopsy has higher yield of

culture & granuloma formation can be demonstrated

Superficial Lymph Node Examination

Superficial lymph node TB → Scrofula Tonsillar, anterior cervical,

submandibular & supraclavicular nodes are commonly involved

Fine needle aspiration: Culture Stain Histology

Excisional biopsy of lymph node → culture +ve in 50% of cases

CSF AnalysisNormal Tuberculosis

TLC None (or few) 10 – 500 cells / cubic mmPMNs predominate early, lymphocytes predominate in majority of cases later

Glucose 40 – 85 mg/dL < 40, rarely < 20 mg/dL

Protein 15 – 45 mg/dL 400 – 5000 mg/dLAcid fast stain Negative Positive in 30% of

casesCulture Negative Positive in 50-70%

of cases

CT/MRI of Brain Normal during early stages Later basilar enhancement &

communicating hydrocephalus Cerebral edema Focal ischemia Tuberculomas (usually in cerebral cortex

& thalamic regions): discrete lesions with surrounding edema (ring enhancement with contrast)

Hydrocephalus

Cerebral Edema

Focal Ischemia

Tuberculomas

Bone biopsy Diagnostic for TB of bones

GI lesion biopsy Jejunum, ileum, appendix, peritoneum etc

Urine Culture +ve in 80 – 90% of cases with renal TB Acid fast stain is +ve 50 – 70% of cases Intravenous pyelogram or CT scan : for mass

lesions, dilatation of proximal ureters, multiple small filling defects, hydronephrosis & ureteral strictures

Disease In HIV Infected Children Rate of TB 30 times higher in HIV

infected children Diagnosis difficult (TST is negative, IGRA

negative, culture confirmation is difficult, clinical features similar to other HIV related infections)

Severe & progressive disease Extrapulmonary disease more common Lobar disease & lung cavitation more

common

Perinatal Disease Infant’s TST becomes positive after 1-3

months Acid fast stains of middle ear discharge,

bone marrow, tracheal aspirate or biopsy tissue (eg liver)

CSF examination (culture yield is low)

Historical Facts About TB

Terms used throughout history: Consumption Phthisis Scrofula Pott’s disease White plague

DNA studies of M. tuberculosis genome suggest that humans acquired it about 6,000 years ago

First acquired in Africa, spread through domestic animals

Initially TB was spread via seals on the beaches of Africa

Hippocrates (460 BC) described the disease as fever, colourless urine, cough with thick sputa, loss of thirst & appetite.

He believed it to be hereditary

Aristotle, on the contrary, believed the disease was contagious

Royal TouchIn the 17th and 18th century, it was believed that the touch of the sovereigns of England or France could cure the disease. So common was this practice of royal healing in France, that scrofula became known as the "mal du roi" or the "King's Evil"

Romantic Disease of The 19th Century

TB represented spiritual purity. George Sand (novelist) doted on her phthitic lover, calling him her “poor melancholy angel”. In a letter she wrote “Chopin coughs

with infinite grace”

5 novels were published in France, expressing the ideals of TB

Robert Koch Discovered Bacillus anthracis, Vibrio

cholera, M. tuberculosis Developed tuberculin (PPD)

Recent Advances In TB

Endobronchial Ultrasound Guided Transbronchial Needle Aspiration (EBUS TBNA)

Two studies1,2 added new insights into pleural and glandular TB

Yield of EBUS TBNA was 93% Potential to replace mediastinoscopy

GeneXpert MTB/RIF The Xpert MTB/RIF is a cartridge-based,

automated diagnostic test that can identify Mycobacterium tuberculosis (MTB) DNA and resistance to rifampicin (RIF) by nucleic acid amplification technique(NAAT)

Sensitivity and specificity of Xpert was found to be 81% and 99% respectively in a study3 , carried out on 1476 clinical specimens including pleural & ascitic fluid, CSF, pus, urine etc.

Pediatric specimens had high sensitivity & specificity (87% and 99% respectively)

1. Ruan SY, Chuang CT, Wang JY, et al. Revisting tuberculous pleurisy: pleural fluid characteristics and diagnostic yield of mycobacterial culture in an endemic area. Thorax 2012;67:822–7.

2. Navani N, Molyneaux PL, Breen RA, et al. Utility of endobronchial ultrasound-guided transbronchial needle aspiration in patients with tuberculous intrathoracic lymphadenopathy: a multicentre study. Thorax 2011;66:889–93.

3. Tortoli E, Russo C, Piersimoni C, et al. Clinical validation of Xpert MTB/RIF for the diagnosis of extrapulmonary tuberculosis. Eur Respir J 2012;40:442–7.