tuberculosis%20-%20pulmonary%20(pediatric)
TUBERCULOSIS - PULMONARY (PEDIATRIC)
Tuberculosis (TB) is caused by Mycobacterium tuberculosis, a gram-positive bacteria with slow growth rate that is enhanced by 6-8% carbon dioxide and temperature of 35-40ºC.
It is primarily transmitted through airborne route.
The number of tubercle bacilli expelled in the air by a TB infected person is directly related to their infectiousness.
TB transmission is rare in children <10 years old due to their inability to expectorate sputum and low TB bacilli load in their sputum.
TB infection in children is usually obtained from an infectious adolescent or adult depending on the closeness and length of contact and the index case's severity of lung involvement and infectiousness.

Tuberculosis%20-%20pulmonary%20(pediatric) Diagnosis

Diagnosis

  • Depends on history, clinical exam and relevant laboratory tests
  • Patients with cough of ≥2 weeks duration and/or abnormal chest radiograph result prompts evaluation for tuberculosis (TB)

Classification

  • Determining the type of pulmonary tuberculosis (PTB) case will aid in appropriate treatment and follow-up
  • Based on the site of disease, result of bacteriological tests, PTB severity and previous intake of antituberculous agents
Sputum Smear-Positive PTB
Any of the following:
  • ≥2 initial sputum smear tests positive for acid-fast bacilli (AFB)
  • 1 sputum smear test positive for AFB plus chest X-ray findings consistent with active PTB, as verified by a clinician
  • 1 sputum smear exam positive for AFB plus sputum culture positive for M tuberculosis
Sputum Smear-Negative PTB
  • Includes patients without smear results
  • At least 3 sputum smear tests negative for AFB, and
  • Chest X-ray findings consistent with active PTB, and
  • Absence of response to any course of broad-spectrum antibiotics, and
  • Physician’s decision to treat with a full course of antituberculous agents
Multidrug Resistant Tuberculosis (MDR-TB)
  • A laboratory diagnosis; should be carried out at referral centers
  • Patient is in contact with a known case of drug-resistant TB
  • Patient is not responding to antituberculous treatment regimen or there is recurrence of TB after adherence to treatment
  • Usually due to noncompliance and incorrect use of anti-TB drugs
  • Patients with active TB disease caused by bacteria that are resistant to at least 2 of the most commonly used drugs for treatment are considered to have MDR-TB
  • Patients with history of treatment for TB infection, drug-resistant TB contacts, residence in a country with high rate of drug resistance, poor response to standard anti-TB drugs, positive sputum smears or culture ≥2 months after starting appropriate therapy are at high risk for drug-resistant TB infection
  • Management should be individualized
Extensively Drug-Resistant Tuberculosis (XDR TB)
  • A type of MDR TB resistant to treatment with Isoniazid and Rifampicin, with additional resistance to any fluoroquinolones and at least 1 of 3 injectable 2nd-line agents used against PTB
  • Patient with MDR TB who is noncompliant and misused anti-TB drugs, or individuals in contact with a known case of XDR TB are at high risk for XDR TB

History

  • In the early stage, most patients with primary tuberculosis (TB) are asymptomatic
  • If child becomes symptomatic, their most common presentation are unremitting cough for >21 days, fever >38°C for 14 days which is not due to any other cause, and weight loss or failure to thrive
  • Progression of TB disease is higher in infants and postpubertal adolescents; disseminated disease is more likely in children <4 years old
    • Patients who are recently infected with TB (eg close contacts of person with active TB disease, persons immigrated from places with high TB rates, children <5 years old with positive TB test) or those with weak immune system (secondary to comorbidities or treatments) have higher risk for active TB disease progression
      • The younger the patient, until the age of 5 years, the higher the risk for TB disease to progress

Physical Examination

  • There are no specific findings that can confirm presence of pulmonary tuberculosis (TB)
  • Growth assessment should also be included
  • Presence of gibbus and enlarged cervical lymphadenopathy may be indicative of extrapulmonary TB and further evaluation may be needed

Laboratory Tests

Purified Protein Derivative (PPD)-Tuberculin Skin Test (TST)
  • Standard screening test for pulmonary tuberculosis (PTB) infection
  • A useful tool in diagnosing PTB disease when used in conjunction with signs, symptoms and other diagnostic tests
  • Intradermal injection of 0.1 mL PPD
  • Amount of induration is measured 48-72 hours after administration
    • Induration started at >72 hours after PPD administration is still considered positive; those seen <24 hours may be caused by immediate hypersensitivity reactions to tuberculin or other constituents of the preparation, hence not considered a positive result
  • Considered positive in the following circumstances:
    • ≥5 mm induration in patients suspected to have tuberculosis (TB) disease, in close contact with known or suspected contagious people with tuberculosis disease, human immunodeficiency virus (HIV)-infected or other immunosuppressed patients, those who are receiving immunosuppressive drugs and patients who have indications for present or previous TB disease
    • ≥10 mm induration in patients who are considered to have an increased likelihood to acquire latent TB infection (LTBI) (eg those living in areas endemic of PTB and those with occupation-related exposure), patients with medical conditions at increased risk to develop LTBI and in patients at increased risk of disseminated TB disease (eg <4 years of age; with other medical conditions like malnutrition, lymphoma, diabetes mellitus; patients born in or who travel in endemic regions of the world; and patients frequently exposed to HIV-infected adults, homeless, institutionalized)
    • ≥15 mm induration in patients ≥4 years of age without any risk factors and for all other individuals
  • A positive PPD-tuberculin skin test indicates infection but does not necessarily indicate an active disease
    • Previous Bacille Calmette–Guérin (BCG) vaccination can cause false-positive TST result, especially if ≥2 BCG vaccines have been given
      • TST result of ≥5 mm is considered positive regardless of a child’s vaccination history
  • A negative finding does not exclude the diagnosis of active PTB
    • Very young age, malnourishment, immunosuppression caused by disease or drugs, viral infections (eg measles, mumps, varicella, influenza), live-virus vaccination, overwhelming TB, or corticosteroids can all decrease patient’s skin test reaction
    • Should be given on the same day as vaccination with live-virus vaccines or after 4-6 weeks from administration of live-virus vaccine
  • Sensitivity develops 3 weeks up to 3 months after the initial infection
Smear Microscopy
  • If PTB is being considered, acid-fast bacilli (AFB) smear should be done, with 3 sputum specimens submitted for evaluation, amounting to at least 3 mL (ideal volume: 5-10 mL)
  • Direct microscopy of the sputum to detect AFB is the most important test in patients with suspected PTB
    • 1st bacteriologic evidence of the presence of mycobacteria
  • Provides presumptive diagnosis of active TB and estimates the number of bacilli on the smear which implies infectivity of the patient
  • Sputum is the best specimen in patients >10 years and who can expectorate
  • Bacterial yields are higher in children >5 years old, adolescents and in children with severe disease
  • 3 sputum specimens must be submitted
  • Gastric aspirate/lavage may be obtained in younger patients who are unable or unwilling to expectorate sputum
    • 3 early morning gastric aspirates are collected on consecutive days
  • Based on studies, sputum induction has a good or even better bacteriological yield than gastric aspirates
  • Each specimen submitted for TB evaluation should undergo culture for M tuberculosis in both liquid and solid media
Mycobacterial Culture
  • Used to confirm the diagnosis and test for drug susceptibility
    • Gold standard in diagnosing TB, however has limited use due to paucibacillary nature of PTB and difficulty of specimen collection in children
    • Both liquid and solid cultures may be done to increase sensitivity for M tuberculosis
    • A liquid culture is both sensitive and with faster results but contamination-prone
    • A solid culture is less sensitive and with slower results but less contamination-prone than liquid culture
  • Recommended as a confirmatory test for suspected TB patients with negative sputum smear microscopy and Xpert MTB/RIF results
  • Recommended for children with increased risk for TB Infection
    • Specimens that can be used include sputum brought about by coughing, induction or nasopharyngeal suctioning, gastric extracts and bronchoalveolar lavage
  • Only way to differentiate M tuberculosis from other nontuberculous mycobacteria
  • Indicated in patients who have one or more of the following:
    • Suspected drug resistance
    • Complicated or severe cases of disease
    • HIV infection
    • Uncertain diagnosis
  • May not be done if epidemiologic, skin test, and X-ray information are consistent with TB
Rapid Molecular Tests
Nuclear Acid Amplification Test (NAAT)
  • May be used when it is difficult to diagnose TB infection and when rapid confirmation is needed to rule out other diagnosis when AFB smear, Xpert MTB/RIF, and TB cultures are negative
  • Not for routine initial evaluation of patients suspected to have TB but is particularly helpful in diagnosing children with pulmonary disease that are immunocompromised
  • Recommended in AFB smear-negative patients with moderate to high probability of TB infection
  • Not recommended for patients with low-risk for TB since false-positive results are common
  • Acceptable NAAT are Hologic Amplified M tuberculosis direct (MTD) test and Cepheid Xpert MTB/RIF test
Xpert MTB/RIF
  • A highly sensitive and specific cartridge-based fully automated NAAT for the detection of M tuberculosis and Rifampicin resistance
    • 68% sensitive, 99% specific when compared to sputum culture
    • 88% sensitive and 98% specific when compared with smear microscopy
    • 94% pooled sensitivity, 98% pooled specificity for Rifampicin resistance
    • 84.9% sensitive for extrapulmonary TB (eg lymph nodes, lung aspirates)
    • 79.5% sensitive for cerebrospinal fluid (CSF) analysis for TB meningitis
  • Recommended as an initial diagnostic tool for the following:
    • Suspected TB patients able to produce sputum samples
    • Patients suspected to have multidrug resistance or HIV-associated TB rather than using other diagnostic tests (eg sputum microscopy, culture, drug susceptibility tests)
    • Seriously ill patients able to produce sputum samples
    • CSF examination of patients suspected to have TB meningitis
    • Patients with non-sputum specimens (gastric lavage fluid, other non-respiratory specimens) at high risk for extrapulmonary TB
  • Recommended as a confirmatory test for suspected TB patients with negative sputum smear microscopy results
  • 1 sputum specimen for Xpert MTB testing is comparable to that of 2 sputum specimens in smear microscopy
T-cell Based Assay/Interferon Gamma Release Assay (IGRA)
  • Detects patient’s T cells generated interferon-γ in response to M tuberculosis antigens
  • IGRAs available:
    • QuantiFERON TB gold in tube (QFT-GIT): Detects the level of IFN-γ in the plasma by means of enzyme-linked immunosorbent assay (ELISA); QuantiFERON-TB gold (QFT-G) test
    • T-SPOT.TB test (T-SPOT): Detects T cells that emit IFN-γ by means of enzyme-linked immunospot (ELISPOT) assay
  • May be used in patients belonging to low-middle class families suspected of TB or latent TB infection
  • Interpret results with caution in children <5 years old and immunocompromised patients
  • IGRA is preferred over TST in patients ≥5 years old with high probability of M tuberculosis infection, LTBI suspected, with low to intermediate risk towards developing TB, BCG-vaccinated or may not follow up for TST result
    • If IGRA is not accessible, a TST may be done instead
    • If the initial test is negative, a second test is performed (eg if the initial test is TST and the result is negative, IGRA, is then performed or vice versa)
    • If the second test is positive, the patient is considered to have M tuberculosis infection
  • There is no need for patients with low risk for TB disease undergo M tuberculosis examination, except in certain conditions (eg as instituted by law), in which IGRA is performed in patients ≥5 years old and a second test is advised
  • May be used in patients >3 years old if necessary
Lateral Flow Urine Lipoarabinomannan (LAM) Assay
  • An immunocapture assay recommended to assist in detection of active TB in HIV-positive patients especially in hospitalized patients with signs and symptoms of TB, severe HIV, or CD4 cell count of <200 cells/mm3
  • May be considered in outpatient setting in patients with signs and symptoms of TB and CD4 cell count of <100 cells/mm3
Drug Susceptibility Testing (DST)
  • In patients who are either positive for AFB smear or Hologic Amplified MTD, a rapid molecular DST for Rifampin, with or without the inclusion of Isoniazid should be done if any of the following are present:
    • History of TB treatment
    • Birthplace or place of residency for 1 year is in a country wherein the average prevalence of TB is ≥20/100,000 or MDR TB is ≥2%
    • With exposure to MDR TB patients
    • With HIV
  • Culture-based DST is the gold standard in the detection of drug resistance and the rapid molecular DST is only for a selected few such as those enumerated above
  • Active TB must be ruled out before initiating LTBI therapy since IGRA and TST cannot differentiate active from latent TB, but only indicate M tuberculosis infection
Xpert MTB/RIF (please see above)
Line-Probe Assay
  • A rapid molecular-based DST that provides result for Isoniazid or Rifampicin within 1-2 days which can be used in deciding the treatment appropriate for the patient
  • Confirmatory diagnostic tool for sputum smear-positive patients and culture-positive TB isolates
  • 1st-line line-probe assays may be used as the initial test instead of phenotypic culture-based DST to detect resistance to Rifampicin and Isoniazid for sputum smear-positive patients or a cultured isolate of M tuberculosis complex
    • Includes INNO-LiPA Rif.TB assay, GenoType® MTBDRplus, GenoType® MTBDRplus version 2 and GenoscholarTM NTM+MDRTB II
  • 2nd-line line-probe assay (eg GenoType® MTBDRsl assay) may be used as the initial test to detect resistance to fluoroquinolones and 2nd-line injectable medications in patients diagnosed with MDR-TB or Rifampicin-resistant TB (RR-TB) instead of phenotypic culture-based DST

Human Immunodeficiency Virus (HIV) Testing

  • Should be offered to pediatric patients with presumptive and diagnosed TB at high risk for HIV infection

Imaging

Chest X-ray
  • Useful in the diagnosis of pulmonary tuberculosis (PTB) but is not specific (98% sensitive, 75% specific for any abnormality suggestive of TB)
  • Lateral X-ray increases the sensitivity of diagnosis in detecting hilar adenopathy
  • Lymphadenopathy or calcification are common findings in primary TB but may also be seen in other viral, bacterial, or fungal infections
  • Presence of uniform stippling in both lungs may highly indicate TB in children
  • The following findings are suggestive of PTB:
    • Persistent lung opacification, miliary pattern may also be noted
    • Enlarged hilar or subcarinal lymph glands
  • Adolescent patients may have findings similar to adult patients (eg pleural effusions, apical infiltrates with cavity formation)
    • May also develop primary disease with collapse lesions and hilar adenopathy

Computed Tomography (CT) Scan

  • May help in diagnosing TB when X-ray results are normal but TB infection is clinically suspected

Screening

Exposure/Latent Infection

  • Latent tuberculosis infection (LTBI) occurs after M tuberculosis-containing infective droplet has been inhaled
  • LTBI is considered in children who have reactive tuberculin skin test (TST) but with no clinical and radiographic manifestations
  • Patients with untreated LTBI have 40% chance of developing TB which is highest during the first 2 years of infection
  • Includes preventive treatment after exposure without evidence of infection and treatment of latent infection
  • There is currently no available definitive examination for the determination of LTBI

Screening and Latent TB Infection Should be Considered in the Following:

  • All household contacts with a smear-positive PTB source case are recommended to be screened for symptoms of disease
    • Includes patients <3-5 years of age; the likelihood of developing disease after infection is much greater in patients <5 years compared to ≥5 years of age
    • Patients ≥5 years of age, if symptomatic
  • With medical conditions (eg HIV, diabetes mellitus, malnutrition, chronic dialysis, leukemia) or with intake of drugs that cause immunosuppression
  • Patients who have chest X-ray findings suggestive of old TB
  • Have purified protein derivative (PPD)-tuberculin skin test results converted to positive after 1-2 years
  • Institutionalized patients in hospitals
  • Patients residing in overcrowded areas (eg orphanages, shelters and prisons)
  • Individuals working in the bacteriology section of the laboratory
  • Those who are living or working in a community that serves as an environment for TB exposure
  • People who came from countries with increased incidence of TB disease

Diagnostic Tests for Suspected Extrapulmonary Tuberculosis

  • Cell counts and laboratory chemistries
  • Adenosine deaminase (ADA)
  • Free Interferon-γ (IFN-γ)
    • For pleural or peritoneal TB
  • AFB smear microscopy
  • Mycobacterial cultures
    • Should be sent to a regional laboratory for genotyping
  • Nucleic acid amplification test
    • Negative results should not rule out the possibility of extrapulmonary tuberculosis
  • Histological examination
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