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

• 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

• ≥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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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 Genoscholar^TM 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

• 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

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

• 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