Pediatric health care providers must be able to identify and test for latent TB in at-risk children and young adults. As part of annual well examinations, providers should screen patients using a validated questionnaire to determine the risk of LTBI;6,7 these questions establish whether a patient is the child of an adult at high-risk of TB; was born in a country at high risk for TB; has traveled to an area at high risk for TB; has close contact with someone with known or suspected TB; is a resident of a high-risk congregate setting; is a health-care worker; or is a member of another at-risk population. If a patient screens positive (defined as any answer affirming a specific risk factor), the patient should undergo TB testing.
Successful TB screening programs are an important component of most pediatric medical homes and may be incorporated into preventive health visits. When children and young adults present to their medical homes less than once a year, gaps in the screening program arise and other public health strategies may need to be relied upon to ensure adequate screening of patients who are at-risk, including school-based and college-based screening programs. No sooner than 6 months prior to arrival on campus, all matriculating college students should complete the TB screening questionnaire. Continuing students need only to be rescreened when their activities require it, such as with studying abroad in a country at high risk for TB or volunteering in a health care role.8
Testing for Tuberculosis
Patients with a positive TB screening questionnaire should undergo either a TST or an interferon-gamma release assay (IGRA), which can either be the QuantiFERON-TB Gold (QFT-G, Cellestis Limited, Carnegie, Victoria, Australia) test or the T-SPOT (Oxford Immunotec Limited, Abingdon, United Kingdom). Either test is optimally performed no sooner than 8 to 10 weeks after the period of at-risk exposure has concluded.4,7,8
The current TST is by Mantoux method in which purified protein derivative (PPD) tuberculin solution is injected intradermally. The TST should be read 48 to 72 hours after injection to detect the cell-mediated, delayed-type hypersensitivity reaction causing measurable induration at the injection site.7,8 Correct interpretation of the TST results requires a trained health care professional to note the size of the area of induration at the injection site with most healthy children and young adults requiring >15 mm induration for the test to be considered positive.7,8 The induration cut-off decreases to 10 mm for patients with a risk factor for LTBI and to 5 mm for patients at high-risk of having or developing TB disease.7,8
IGRAs are blood tests that detect interferon-gamma (IFN-gamma) release from a patient's CD4+ T-lymphocytes after stimulation with M. tuberculosis complex antigens. Both commercially available IGRAs are enzyme-linked immunosorbent tests on either whole blood (QuantiFERON-TB Gold In-tube assay) or peripheral blood mononuclear cells (T-SPOT.TB assay). Both tests are considered positive when the INF-gamma response exceeds the test cut-off threshold after subtracting the negative control sample value run at the same time.9 Both the TST and the IGRAs are imperfect TB testing methods. Neither method has a clear advantage regarding test sensitivity, although IGRAs offer greater specificity.
Anergy, or lack of response, to the PPD derivative is a specific disadvantage that can arise in certain circumstances with the TST. Anergy can arise in the setting of active TB infection as well as in patients with other severe infections, inflammatory conditions, and/or malnourishment and in patients with HIV or who take immunosuppressive medication. One additional risk of anergy with the TST is recent receipt of live virus vaccinations, including the routine childhood immunizations measles, mumps, and rubella and varicella.1 TST can be performed on the same day as the live virus vaccination and no sooner than 1 month after live viral vaccination.1 Most patients who will have anergy to the PPD derivative will also be more likely to have a false-negative IGRA.9
The decision to perform a TST versus an IGRA begins with a patient's age; all patients younger than age 5 years, Bacillus Calmette–Guérin (BCG) vaccinated or not, should first undergo a TST. All patients older than age 5 years who have been vaccinated against BCG or who are unlikely to return for a TST reading should first undergo an IGRA. Among patients older than age 5 years who are likely to return for a TST reading, either a TST or IGRA is considered acceptable TB testing. Secondary IGRA may be performed as further supportive evidence of either a positive or negative TST depending on the original clinical suspicion; repeat IGRA is necessary only if the first IGRA was indeterminate.4
If either the TST of IGRA are positive, a patient should undergo medical examination and chest radiography to diagnose either LTBI or active pulmonary TB. Although sputum culture is the gold standard for diagnosis, it can take up to 10 weeks for adequate growth4 and is ultimately positive in fewer than one-half of all pediatric clinical cases.2 Microscopic evaluation by acid-fast staining is quick but often negative even in culture-proven cases.10 There are rapid nucleic acid amplification tests available through reference laboratories that are sensitive and specific for detecting M. tuberculosis and rifampin resistance, but the index of suspicion for TB specifically would have to be high enough to justify sending it prior to any other positive testing.
Upping the diagnostic ante: the toolkit for diagnosis when pneumonia is more than community-acquired pneumonia. Knowing that a TST, IGRA, and sputum acid-fast stain can all be negative in cases of TB, it is no surprise to learn that one study conducted in New York revealed a median delay of 15 days from presentation to health care to initiation of therapy for all comers.11 In the illustrative case, the patient was initially treated for presumptive community-acquired pneumonia (CAP), and it was his failure to improve regardless of antimicrobial coverage that forced us to broaden the differential sequentially and move forward with further testing. The Infectious Disease Society of America has guidelines to aid in the decision to pursue more invasive or higher risk evaluations in any patient with pneumonia who fails to improve on empiric therapy for CAP. In both adults and children, worsening of symptoms or failure to defervesce 48 to 72 hours after starting antimicrobial therapy warrants re-imaging for progression of disease and broadening of coverage.12,13 However, up to 25% of adults can take 6 days to respond to appropriate therapy, and prior to any further testing it is recommended that a repeat history be obtained with careful attention to specific risk factors for atypical microbes.12 Although chest CT, thoracentesis, and BAL comprise the toolkit for pursuing definitive diagnosis in nonresponders, there is not strong evidence or language about how soon to commit or which to do first.
CT is the modality of choice for evaluating lung parenchyma. In adults with nonresponding pneumonia, a chest CT is recommended prior to any procedures to help characterize the process and plan for biopsy/lavage.14 As children are more sensitive to ionizing radiation, CT should be reserved for when ultrasound and roentgenography are not able to provide sufficient detail or direct therapeutic intervention. Specifically, chest CT without IV contrast can characterize cavitations, abscesses, congenital malformations, and masses as reasons for treatment failure in cases of pneumonia.
Whereas chest CT offers greater clarity when an anatomic diagnosis must be rendered, bronchoscopy with BAL (or thoracentesis in cases where an effusion is present) can provide certainty regarding the causative organism. Prior to bronchoscopy, it is appropriate to study induced sputum samples. Although young children are less able to produce sputum, children older than age 5 years and adolescents are frequently able to comply.4 Tuberculosis can be diagnosed by sputum staining and eventually culture of affected adults and children, negating the need for bronchoscopy. For the nonresponding case of pneumonia with negative or uninterpretable sputum studies, BAL is preferred over percutaneous parenchyma aspiration and open lung biopsy. In one prospective study of children with CAP, tandem sputum and BAL cultures were positive in 37.5% and 73.8%, respectively.13 Although bronchoscopy with BAL is indicated in the testing of many pulmonary diseases, its utility specifically for infectious diagnostic purposes in adults with pneumonia is less well studied.