tuberculosis%20-%20pulmonary
TUBERCULOSIS - PULMONARY
Tuberculosis (TB) suspect is any one who has signs or symptoms suggestive of TB (eg >2 weeks productive cough).
Definite TB is considered in patients with culture or molecular line probe assay positive for Mycobacterium tuberculosis, or in patients with at least 1 sputum smear positive for acid-fast bacilli.
TB cases are also classified based on the disease anatomical site, bacteriological results (including drug resistance), previous treatment history and patient's HIV status.
Pulmonary TB is a case of TB that involves the lung parenchyma.
Miliary TB is considered as PTB since lung lesions are also seen.
TB in the pleural effusion, mediastinal and/or hilar lymph nodes with no evidence of abnormalities in the chest x-ray are considered extrapulmonary TB.
Patients presenting with both PTB and extrapulmonary TB are classified as a case of PTB.

Diagnosis

  • Most common symptom of pulmonary tuberculosis (PTB) is cough ≥2 weeks that is productive & may be accompanied by both/either:
    • Respiratory symptoms: Shortness of breath, chest pains, hemoptysis
    • Constitutional symptoms: Loss of appetite, unexplained weight loss, fever, night sweats, fatigue
  • Important to ask about history of previous treatment w/ anti-TB drugs
    • Has higher risk for drug resistance, including multidrug-resistant tuberculosis (MDR-TB)

Evaluation

  • Basis of the management in each patient
New Patient
  • Patients who never had tuberculosis (TB) treatment or have taken anti-TB regimen for <1 month
  • Assumed to be drug susceptible unless the patient is from an area w/ high prevalence of Isoniazid resistance or if the patient had active TB after contact w/ a documented multi-drug resistant strain of TB (MDR-TB) patient
  • Patients who will have MDR-TB at any time during the therapy will be considered as a treatment failure
Previously Treated Patient
  • Has history of taking anti-TB drugs for ≥1 month & currently smear or culture positive again
  • Further subclassified based on the outcome of their most recent treatment course
    • Relapse: Patient has been cured or most recent prior treatment was completed
    • Failure: Most recent prior treatment has failed
    • Default: Treatment was interrupted for ≥2 consecutive months
  • Strongly determines resistance of drugs
    • Timely detection of multi-drug resistance (MDR) & start of MDR regimen w/ 2nd-line drugs gives a better likelihood of cure & prevents development & transmission of further resistance
    • Incidence of MDR is higher in previously treated patients than in new patients
      • Patients returning after defaulting or relapsing has lesser MDR rates than patients who had treatment failure
    • Patients w/ prior treatment failure should be given an empirical MDR regimen while waiting for the results if conventional drug susceptibility testing (DST) was used
      • Prevents clinical deterioration of the patient & decreases risk of transmission to contacts
    • National TB Control Program (NTP) should use country-specific drug resistance data of patient groups on failure, relapse & default to know the level of MDR
    • High MDR levels are noted in patients:
      • Treated in poorly operating NTP
      • Living w/ human immunodeficiency virus (HIV)
      • W/ type 2 diabetes mellitus
      • W/ history of using poor or unknown quality of anti-TB drugs
      • Exposed in institutions w/ high-prevalence rate or outbreak of MDR
      • W/ conditions associated w/ malabsorption or rapid-transit diarrhea
      • Whose prior regimen included Rifampicin throughout the course
      • Who still has positive sputum smear at mth 2 or 3 of treatment

Laboratory Tests

Sputum Smear Microscopy
  • Recommended for all individuals highly suspected of pulmonary tuberculosis (PTB) 
  • 3 sputum specimens are submitted for evaluation, amounting to at least 3 mL (ideal volume: 5-10 mL)
    • Patient must submit at least 1 early-morning sputum sample which usually has the highest yield
    • 2 sputum samples submitted on the same day are comparable to 2 consecutive days-sputum specimens
      • W/ similar sensitivity (63-64%) & specificity (98%) rates
  • Recommended also for patients w/ chest X-ray suggestive of TB
  • PTB cases without results of sputum smear are classified as “smear not done”
  • Also used in monitoring treatment response of patients
  • Fluorescence microscopy preferred over conventional microscopy because of its higher sensitivity & better time efficiency
  • Individuals suspected to have PTB, who are either negative for AFB smear or unable to provide appropriate sputum samples are recommended to still submit proper sputum specimens via induction, than having to obtain them through flexible bronchoscopy, which is recommended for individuals suspected to have PTB who are incapable of providing induced sputum specimens
  • Individuals suspected to have PTB who are incapable of providing induced sputum specimens are recommended to undergo flexible bronchoscopy technique to yield samples
  • If there is a need for an immediate diagnosis, transbronchial biopsy (TBB) may be done
  • Sputum samples of post-bronchoscopy PTB-suspected patients should be sent for culture & AFB smear
  • Patients under miliary TB consideration, with negative AFB smear, with no other available specimens to submit for laboratory diagnosis & unable to provide induced sputum, are recommended to have specimens obtained by means of flexible bronchoscopy
  • Samples should include TBB and/or bronchial brushings
  • AFB smear is indicated on specimens from sites that are being considered for extrapulmonary TB
Smear-Positive Pulmonary Tuberculosis (PTB)
  • Considered smear-positive if ≥1 sputum smear specimens at the start of treatment in countries w/ well functioning external quality assurance (EQA) system are positive for acid-fast bacilli (AFB) 
  • In countries w/ no functional EQA, a smear-positive PTB is considered when:
    • ≥2 initial sputum smear exams are positive for AFB, or
    • 1 sputum smear exam is positive for AFB w/ abnormalities consistent w/ active PTB in chest X-ray, or
    • 1 sputum smear positive for AFB w/ culture positive for M tuberculosis
Smear-Negative Pulmonary Tuberculosis (PTB)
  • Considered in patients w/ negative sputum smear but w/ positive culture for M tuberculosis or when at least 2 sputum samples at the start of treatment in countries w/ a functional EQA system are negative for AFB
    • To confirm the diagnosis of TB, sputum culture for M tuberculosis is advised in patients who live in areas w/ human immunodeficiency virus (HIV) prevalence of >1% in pregnant women or ≥5% in TB patients that have smear-negative sputum
  • Also regarded in patients who are being treated by a clinician w/ a full course of anti-TB regimen w/ abnormalities in chest X-ray consistent w/ active PTB, & patient is either positive for HIV or if w/ negative or unknown HIV status that lives in area of low HIV prevalence, has no improvement in response to a course of broad-spectrum antibiotics (excluding anti-TB drugs & fluoroquinolones & aminoglycosides)
Rapid Molecular Tests
  • Nucleic acid amplification tests (NAATs) are recommended for better detection of M tuberculosis
  • An initial pulmonary sample should undergo NAAT
    • In patients who are AFB smear-positive & with negative NAAT, TB disease is improbable
    • In patients who are AFB smear-negative & with moderate to high index of having TB disease, a positive NAAT enables the assumption of TB disease, however, a negative NAAT does not disregard TB disease
    • In patients who are unlikely to have TB disease, NAAT is not recommended since the yield of results that are false-positive are very common
    • Acceptable NAAT are Hologic amplified M tuberculosis direct (MTD) test & Xpert MTB/RIF test
  • NAAT is also performed on specimens from patients in whom extrapulmonary TB is a consideration
    • A negative result should not rule out the possibility of extrapulmonary TB
  • Older NAATs have low sensitivity & w/ negative predictive value for smear-negative & extrapulmonary TB
Xpert MTB/RIF
  • A highly sensitive & specific cartridge-based fully automated NAATs for the detection of M tuberculosis & Rifampicin resistance
    • 68% sensitive, 99% specific when compared to sputum culture; 88% sensitive & 98% specific when compared w/ 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 CSF analysis for TB meningitis
  • Recommended as an initial diagnostic tool for the following:
    • Suspected TB patients able to produce sputum samples
    • Adult patients w/ risk factors for multi-drug resistance
    • Adult patients w/ comorbidities (HIV infection, immunocompromised)
    • Pediatric patients suspected to have multidrug resistance or HIV-associated TB rather than using other diagnostic tests (eg sputum smear testing, culture, drug susceptibility tests)
    • CSF examination of patients suspected to have TB meningitis
  • Recommended as a confirmatory test for suspected TB patients w/ negative sputum smear microscopy results
  • May also be used as an initial diagnostic tool for non-sputum specimens (gastric lavage fluid, other non-respiratory specimens) from patients at high risk for extrapulmonary TB
Hologic Amplified Mycobacterium Tuberculosis Direct (MTD) Test
  • A nucleic acid probe test for the identification of M tuberculosis complex rRNA from sputum, bronchial or tracheal specimens
  • A negative result does not mean that M tuberculosis complex is not present since the procedure may be influenced by different factors (eg handling of samples, laboratory errors)
Interferon-Gamma Release Assay (IGRA)
  • A diagnostic blood test used to identify a patient’s immune reactivity to M tuberculosis
  • May be considered for the initial diagnosis of children suspected to have TB; not recommended for the initial diagnosis in adults
  • Tuberculin testing still preferred over IGRA for patients belonging to low-middle class families
  • In determining the presence of latent TB infection (LTBI)
    • IGRA is preferred over tuberculin skin test (TST) in patients ≥5 years old who are likely infected w/ M tuberculosis, those w/ low-intermediate risk of disease progression, patients highly suspected of LTBI & previously vaccinated w/ BCG or may not follow-up for TST reading
      • Note: TST may be performed instead if IGRA is unavailable or not preferred by the patient
    • May perform IGRA instead of TST in patients ≥5 years of age at high risk for M tuberculosis, those at low to intermediate risk for disease progression, & if LTBI test is warranted
    • For patients at high risk of disease progression, IGRA may be performed if initial TST is negative
      • May consider 2nd test result as confirmatory of M tuberculosis infection if positive
    • There is no need for M tuberculosis examination for individuals w/ low risk of having the disease, except in certain instances (eg as instituted by law), wherein patients ≥5 years old should undergo IGRA preferebly (or TST as an alternative), w/ those whose results revealed infection should undergo another test (TST or IGRA, whichever is not used initially) for confirmation
    • Active TB infection should be ruled out prior to LTBI treatment, since IGRA & TST only indicate M tuberculosis infection, without differentiating between active & latent
Tuberculin Skin Testing (TST, Mantoux Method)
  • Recommended for the initial diagnosis of children suspected to have TB, but w/ no history of contact w/ persons w/ active TB disease
  • Not recommended as an initial diagnostic tool for adults
  • Also used as a screening examination for pediatric patients in contact w/ persons w/ active PTB
  • Is considered positive in the following instances:
    • ≥5 mm induration in immunocompromised patients, w/ diagnostic evaluation indicating current or previous TB, individuals who are in close contact w/ people w/ PTB, those who are receiving immunosuppressive agents
    • ≥10 mm induration for those at increased risk for LTBI & those w/ medical conditions that predispose them to progress from LTBI to TB disease
    • ≥15 mm induration for all other individuals
  • A positive skin test is not conclusive of an active TB disease; other confirmatory tests should be performed
Culture
  • Used for definitive diagnosis of TB in patients w/ negative sputum smear, especially in areas w/ high HIV prevalence
  • Also advised in patients in whom drug resistance is likely considered
  • Specimen should undergo culture for M tuberculosis in both liquid and solid media
    • Liquid system detects mycobacteria more & increases the case yield by 10%, & provides DST result within 10 days as compared to solid media
  • Also performed on specimens from patients in whom extrapulmonary TB is suspected
    • Positive results can be used for documentation of extrapulmonary TB & assist in patient evaluation, but a negative result should not rule out the possibility of extrapulmonary TB
  • A culture isolate indicative of mycobacterial growth should be sent to a regional laboratory for genotyping
Drug Susceptibility Testing (DST)
  • Ideally done to all patients at the start of the treatment to identify & provide the most appropriate therapy
  • Should be done at or prior to the start of treatment in:
    • New patients who had active TB after contact w/ a documented multidrug-resistant tuberculosis (MDR-TB) patient
    • All previously treated patients, especially in patients w/ sputum smear-positive after 3 months therapy, treatment failure, patients lost to follow-up, & those w/ disease relapse after treatment
    • Patients living w/ HIV
    • HIV-infected TB patients w/ CD4 counts <200 cells/mm3
    • All new patients in countries w/ >3% MDR-TB level in new patients
  • Should be performed for at least Isoniazid & Rifampicin
  • In patients who are either positive for AFB smear or hologic amplified MTD, a rapid molecular DST for Rifampin, w/ or without the inclusion of Isoniazid is recommended, if any is 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 that of MDR-TB is ≥2%
    • Exposed to MDR-TB patients
    • With HIV disease
    • Culture-based DST is the gold standard in the detection of drug resistance & the rapid molecular DST is only for a selected few such as those enumerated above
  • Conventional DST provides result w/in a week for liquid media or month for solid media; therefore, patients should be given empirical regimen while awaiting the results
    • Shorter waiting time for DST results may stop continued spread of multidrug-resistant (MDR), prevent increase of resistance, & avoid increased risk of patient defaulting from treatment due to adverse effects of unnecessary empiric drugs
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 & culture-positive TB isolates
  • Not to be used as an initial test for TB detection; should be used together w/ culture & drug susceptibility testing
  • GenoType M tuberculosis drug-resistant second-line assay (MTBDRsl) or GenoType MTBDRsl line probe assay is recommended as a primary test to identify the presence of resistance to fluoroquinolones & 2nd-line injectable medications in patients diagnosed with MDR-TB or Rifampicin-resistant TB (RR-TB)
Phenotypic Drug Susceptibility Testing for Anti-TB Drugs
  • Testing for all fluoroquinolones & injectable aminoglycosides are recommended for Rif-resistant & MDR-TB patients
Tests for Extrapulmonary Tuberculosis
  • Cell counts & chemistries are performed on samples from extrapulmonary TB-infected regions (eg abdominal, pleural, joint fluids, etc)
  • Measurement of adenosine deaminase (ADA) may be considered for patients suspected to have TB meningitis, pleural, peritoneal or pericardial TB
  • Measurement of interferon-γ (IFN-γ) may be used for patients suspected of pleural or peritoneal TB
  • Histologic examination may also be considered, together with AFB smear microscopy, mycobacterial cultures & NAAT

Imaging

Chest X-ray
  • Sensitive but nonspecific test to detect tuberculosis (TB) [98% sensitive, 75% specific for any abnormality suggestive of TB]
  • Cannot establish the diagnosis of TB alone
  • Used to evaluate patients w/ negative sputum smears &/or negative Xpert MTB/RIF, & identify other possible diagnosis
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