1. New TB Guidelines Deborah McMahan, MD Health Commissioner
Fort Wayne Allen County Department of Health

2. Agenda Diagnosis of: Latent TB infection (LTBI) Pulmonary tuberculosis
Extrapulmonary tuberculosis

3. Diagnosis of LTBI

4. Latent TB
The purpose of testing for latent TB infection (LTBI) is to identify folks who should be treated to prevent reactivation at a later date.
There are 2 major benefits of treating LTBI:
Treating LTBI prevents progression to active TB disease in the individual.
Prevents transmission (each active case infects 15 people on average before identified and started on tx.

5. Latent TB
Average person with latent TB has a about a 5% to 10% chance of developing active TB.
 The greatest risk of progression is during the first 2 years following exposure to an active case. 

6. Latent TB
 Relative risk measures the strength of association between an exposure and a disease. 
If the relative risk result is:
<1 the exposure decreases risk of disease
0 the exposure has no effect on risk of disease
>1 the exposure increases risk of disease

7. Risk Factors for Progression
 Advanced untreated HIV
Close contacts
Old unhealed TB on x-ray 5.2
Treatment with TNF-α inhibitor 2
Diabetes uncontrolled
Silicosis

8. Risk Factors for Progression
Other risk factors include:
Age less than 4 years
Smoking
Low body weight
Renal failure
Transplant
Prednisone treatment at doses of 15 mg/day for more than 1 month

9. Definitions
Sensitivity is the ability of a test to correctly identify those with the disease (true positive rate)
Specificity is the ability of the test to correctly identify those without the disease (true negative rate).

10. Definitions
Positive predictive value is the probability that subjects with a positive screening test truly have the disease.
Negative predictive value is the probability that subjects with a negative screening test truly don't have the disease.

11. Diagnosis of Latent TB Tuberculin skin Test
Sensitivity is high (95%–98%).
False-negative reactions occur more frequently in:
Infants and young children
Early (<6–8 weeks) after infection
Persons having recently received viral vaccination
Persons with clinical conditions associated with immunosuppression or overwhelming illness (including TB)
Persons with recent viral and bacterial infections
Association with treatment with immunosuppressive drugs (eg, high-dose corticosteroids, TNF inhibitors).

12. Diagnosis of Latent TB Tuberculin skin Test
The specificity is 29 to 39%
The positive predictive value 2.7 to 3.1%
The negative predictive value 99 to 100%

13. Diagnosis of Latent TB - IGRAs
IGRAs use a single specimen of peripheral blood that is drawn and incubated overnight with specific antigens for M. tuberculosis; interferon-γ production is then determined.
The QFT test measures the amount of interferon-γ in the supernatant of a cell suspension, whereas the T-SPOT test determines the number of cells producing interferon-γ with the use of an ELISpot assay.

14. Diagnosis of Latent TB IGRAs
The pooled sensitivity of IGRAs for predicting the development of active disease within several years after exposure was 80 to 90%,
The specificity 56 to 83%
The positive predictive value 4 to 8%
The negative predictive value 99 to 100%.

15. Diagnosis of Latent TB - IGRAs
IGRAs appear to be somewhat more specific and less sensitive for predicting future disease than the tuberculin skin test, but the differences are modest.
Both types of test have low positive and high negative predictive values.
Because both IGRAs and the TST rely on an intact immune response, both are likely to have reduced sensitivity when used in persons with immunosuppression.

16. Diagnosis of Latent TB - IGRAs
Whereas the tuberculin skin test may be more likely to identify persons with longstanding cellular immune responses to TB antigens, IGRAs are more likely to be positive in persons who have recently been infected with M. tuberculosis, which is a group at particularly high risk for progression to disease.
Also no cross reactivity with BCG

17. Diagnosis of Latent TB
Remember, A negative reaction to a TST or IGRA does not exclude the diagnosis of LTBI or TB disease.
The decisions about medical or public health management should include epidemiological, historical, and other clinical information when using IGRA or TST results.
Decisions should not be based on TST or IGRA results alone.

18. Guideline Development Methodology

19. Methodology
American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America searched, selected, and synthesized relevant evidence to draft recommendations that were then graded by the group.
David M. Lewinsohn Michael K. Leonard Philip A. LoBue David L. Cohn Charles L. Daley Ed Desmond Joseph Keane Deborah A. Lewinsohn Ann M. Loeffler Gerald H. Mazurek Richard J. O’Brien Madhukar Pai Luca Richeldi Max Salfinger Thomas M. Shinnick Timothy R. Sterling David M. Warshauer Gail L. Woods

20. Methodology They used the GRADE approach Grading Recommendations
Assessment
Development
Evaluation

21. Strong Recommendation
Patient Perspective: Most individuals in this situation would want the recommended course of action, and only a small proportion would not. Clinician Perspective: Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. Policy: The recommendation can be adopted as policy in most situations.

22. Conditional (Weak) Recommendation
Patient Perspective: The majority of individuals in this situation would want the suggested course of action, but many would not. Clinician Perspective: Recognize that different choices will be appropriate for individual patients and that you must help each patient arrive at a management decision consistent with his or her values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their values and preferences. Policy: Policymaking will require substantial debate and involvement of various stakeholders.

23. Methodology Recommendations were made for diagnosing:
Latent TB infection (LTBI)
Pulmonary tuberculosis
Extrapulmonary tuberculosis
Their recommendations for diagnostic testing for LTBI are based upon the likelihood of infection with Mtb and the likelihood of progression to TB disease if infected

24. High Risk for Infection
Close contacts to an active case
Immigrants from high prevalence countries
Homeless
Injection Drug Users

25. Risk for Progression to Disease
Low Risk – No Risk Factors
Intermediate Risk (RR 1.3 to 3):
Clinical predisposition:
Diabetes
Chronic renal failure
IVDU

26. Risk for Progression to Disease
High Risk (RR 3 to 10):
Children less than 5 years of age
HIV
Immunosuppressive therapy
Chest x-ray consistent with prior infection
Silicosis

27. Guidelines for Testing for Latent TB Infection

28. Strong Recommendation
They recommend performing an IGRA rather than a TST in individuals 5 years or older who meet the following criteria:
are likely to be infected with Mtb
have a low or intermediate risk of disease progression
it has been decided that testing for LTBI is warranted
either have a history of BCG vaccination or are unlikely to return to have their TST read
Remarks: A TST is an acceptable alternative, especially in situations where an IGRA is not available, too costly, or too burdensome.

29. Conditional Recommendation
They suggest performing an IGRA rather than a TST in all other individuals 5 years or older who are:
likely to be infected with Mtb
who have a low or intermediate risk of disease progression
and in whom it has been decided that testing for LTBI is warranted
Remarks: A TST is an acceptable alternative, especially in situations where an IGRA is not available, too costly, or too burdensome.

30. Insufficient Data
There are insufficient data to recommend a preference for either a TST or an IGRA as the first-line diagnostic test in individuals 5 years or older who are:
likely to be infected with Mtb
who have a high risk of progression to disease
in whom it has been determined that diagnostic testing for LTBI is warranted.

31. Conditional Recommendation
Testing of people with low risk of being infected and disease progression but are required to be tested for job, etc. They suggest performing an IGRA instead of a TST in individuals 5 years or older Remarks: A TST is an acceptable alternative in settings where an IGRA is unavailable, too costly, or too burdensome.

32. Conditional Recommendation
They suggest a second diagnostic test if the initial test is positive in individuals 5 years or older Remarks: The confirmatory test may be either an IGRA or a TST. When such testing is performed, the person is considered infected only if both tests are positive.

33. Conditional Recommendation
They suggest performing a TST rather than an IGRA in healthy children <5 years of age for whom it has been decided that diagnostic testing for LTBI is warranted Remarks: In situations in which an IGRA is deemed the preferred diagnostic test, some experts are willing to use IGRAs in children over 3 years of age.

34. Conditional Recommendation
They suggest performing a TST rather than an IGRA in healthy children <5 years of age for whom it has been decided that diagnostic testing for LTBI is warranted Remarks: In situations in which an IGRA is deemed the preferred diagnostic test, some experts are willing to use IGRAs in children over 3 years of age.

35. https://academic. oup. com/cid/article/doi/10

36. World TB Day Quizlet
45 year old Phillippino presents for green card physical. His Past Medical History is remarkable for hypertension and chronic renal failure. He has no symptoms but his shoe size is 11 medium.
What test do you recommend for evaluating for LTBI?
IGRA; high risk of infection and intermediate risk for progression

37. World TB Day Quizlet
Eighteen year old girl whose grandmother was diagnosed with smear positive active TB. No symptoms but does not seem to like you very much and she is homeless
What test do you recommend for evaluating for LTBI?
IGRA; high risk of infection and intermediate risk for progression but not likely to return

38. Guidelines for Testing for Active TB Disease

39. Strong Recommendation
We recommend that acid-fast bacilli (AFB) smear microscopy be performed, rather than no AFB smear microscopy, in all patients suspected of having pulmonary TB. Providers should request a sputum volume of at least 3 mL, but the optimal volume is 5–10 mL. Concentrated respiratory specimens and fluorescence microscopy are preferred. Remarks: False-negative results are sufficiently common that a negative AFB smear result does not exclude pulmonary TB. Similarly, false-positive results are sufficiently common that a positive AFB smear result does not confirm pulmonary TB.

41. Conditional Recommendation
They suggest that both liquid and solid mycobacterial cultures be performed, rather than either culture method alone, for every specimen obtained from an individual with suspected TB disease (conditional recommendation, low-quality evidence). Remarks: The conditional qualifier applies to performance of both liquid and solid culture methods on all specimens. At least liquid culture should be done on all specimens as culture is the gold standard microbiologic test for the diagnosis of TB disease. The isolate recovered should be identified according to the Clinical and Laboratory Standards Institute guidelines and the American Society for Microbiology Manual of Clinical Microbiology.

42. Mycobacterium tuberculosis colonies on Löwenstein-Jensen solid medium
TB growth in liquid medium

43. Conditional Recommendation
They suggest performing a diagnostic nucleic acid amplification test (NAAT), rather than not performing a NAAT, on the initial respiratory specimen from patients suspected of having pulmonary TB.
Remarks: In AFB smear-positive patients, a negative NAAT makes TB disease unlikely. In AFB smear-negative patients with an intermediate to high level of suspicion for disease, a positive NAAT can be used as presumptive evidence of TB disease, but a negative NAAT cannot be used to exclude pulmonary TB.

44. Strong Recommendation
They recommend performing rapid molecular drug susceptibility testing for rifampin with or without isoniazid using the respiratory specimens of persons who are either AFB smear positive or Hologic Amplified MTD positive and who meet one of the following criteria:
have been treated for tuberculosis in the past,
were born in or have lived for at least 1 year in a foreign country with at least a moderate tuberculosis incidence (≥20 per ) or a high primary multidrug-resistant tuberculosis prevalence (≥2%)
are contacts of patients with multidrug-resistant tuberculosis, or
are HIV infected.
Remarks: This recommendation specifically addresses patients who are Hologic Amplified MTD positive because the Hologic Amplified MTD NAAT only detects TB and not drug resistance; it is not applicable to patients who are positive for types of NAAT that detect drug resistance, including many line probe assays and Cepheid Xpert MTB/RIF.

45. Molecular Drug Susceptibility
The test simultaneously detects Mycobacterium tuberculosis complex (MTBC) and resistance to rifampin (RIF) in less than 2 hours.
In comparison, standard cultures can take 2 to 6 weeks for MTBC to grow and conventional drug resistance tests can add 3 more weeks.
Quicker results provide timely that aids in selecting treatment regimens and reaching infection control decisions quickly.

46. Conditional Recommendation
They suggest mycobacterial culture of respiratory specimens for all children suspected of having pulmonary TB.
Remarks: In a low incidence setting like the United States, it is unlikely that a child identified during a recent contract investigation of a close adult/adolescent contact with contagious TB was, in fact, infected by a different individual with a strain with a different susceptibility pattern. Therefore, under some circumstances, microbiological confirmation may not be necessary for children with uncomplicated pulmonary TB identified through a recent contact investigation if the source case has drug- susceptible TB.

47. Conditional Recommendation
They suggest sputum induction rather than flexible bronchoscopic sampling as the initial respiratory sampling method for adults with suspected pulmonary TB who are either unable to expectorate sputum or whose expectorated sputum is AFB smear microscopy negative

48. Conditional Recommendation
They suggest flexible bronchoscopic sampling, rather than no bronchoscopic sampling, in adults with suspected pulmonary TB from whom a respiratory sample cannot be obtained via induced sputum.
Remarks: In the committee members’ clinical practices, bronchoalveolar lavage (BAL) plus brushings alone are performed for most patients; however, for patients in whom a rapid diagnosis is essential, transbronchial biopsy is also performed.

49. What is a NAAT?
Nucleic acid amplification test (NAAT) is a testing method that detects the genetic material (nucleic acid) of the bacteria causing the infection.
It does this in part by amplifying or making numerous copies of the genetic material so that the detection system can identify the presence of the bacteria. 

50. Conditional Recommendation
They suggest that postbronchoscopy sputum specimens be collected from all adults with suspected pulmonary TB who undergo bronchoscopy. Remarks: Postbronchoscopy sputum specimens are used to perform AFB smear microscopy and mycobacterial cultures.

51. Conditional Recommendation
They suggest flexible bronchoscopic sampling, rather than no bronchoscopic sampling, in adults with suspected miliary TB and no alternative lesions that are accessible for sampling whose induced sputum is AFB smear microscopy negative or from whom a respiratory sample cannot be obtained via induced sputum

52. Conditional Recommendation
Remarks: Bronchoscopic sampling in patients with suspected miliary TB should include bronchial brushings and/or transbronchial biopsy, as the yield from washings is substantially less and the yield from BAL unknown. For patients in whom it is important to provide a rapid presumptive diagnosis of tuberculosis (ie, those who are too sick to wait for culture results), transbronchial biopsies are both necessary and appropriate..

53. World TB Day Quizlet AFB smear, culture and PCR q 8 hours times three.
It is July 4th weekend and a new intern is on call at the hospital. They call you all excited that they have a patient with productive cough, fever, night sweats and a 10 pound weight loss. And, they were born in Burma. They think she has TB and are asking you what they should order?
What test (s) do you recommend?
AFB smear, culture and PCR q 8 hours times three.

54. World TB Day Quizlet Are you concerned it is pulmonary TB or miliary?
Your friendly ID doc calls you about a patient whom she believes has TB but only has a dry cough. She wants to bronch him but he is on coumadin and his INR is 4. They want to know if you would be okay if they just tried to induce sputum or do you think they should try and bronch him despite his INR.
What other info do you need to know to answer?
Are you concerned it is pulmonary TB or miliary?

55. Guidelines for Testing for Extrapulmonary TB

56. Conditional Recommendation
They suggest that cell counts and chemistries be performed on amenable fluid specimens collected from sites of suspected extrapulmonary TB. Remarks: Specimens that are amenable to cell counts and chemistries include pleural, cerebrospinal, ascitic, and joint fluids.

57. Conditional Recommendation
They suggest that adenosine deaminase (ADA) levels be measured, rather than not measured, on fluid collected from patients with suspected pleural TB, TB meningitis, peritoneal TB, or pericardial TB. Also suggest that free IFN-γ levels be measured, rather than not measured, on fluid collected from patients with suspected pleural TB or peritoneal TB

58. What is ADA?
Adenosine deaminase (ADA) is a protein that is produced by cells throughout the body and is associated with the activation of lymphocytes, a type of white blood cell that plays a role in the immune response to infections. 
Activity of this enzyme increases in TB patients.

59. How is ADA Collected?
A sample of pleural fluid is collected by a healthcare practitioner with a syringe and needle using a procedure called thoracentesis
Rarely, other body fluid samples, such as peritoneal or cerebrospinal fluid (CSF), are collected using procedures specific to the fluid type.

60. What is Interferon Gamma ?
Interferon gamma (IFN-γ), a cytokine produced by a variety of cells is involved in the immune response against M. tuberculosis.
It activates the production of other cytokines and molecules that kill mycobacterium.

61. Conditional Recommendation
They suggest that AFB smear microscopy be performed, rather than not performed, on specimens collected from sites of suspected extrapulmonary TB. Remarks: A positive result can be used as evidence of extrapulmonary TB and guide decision making because false-positive results are unlikely. However, a negative result may not be used to exclude TB because false-negative results are exceedingly common.

62. Conditional Recommendation
They recommend that mycobacterial cultures be performed, rather than not performed, on specimens collected from sites of suspected extrapulmonary TB. Remarks: A positive result can be used as evidence of extrapulmonary TB and guide decision making because false-positive results are unlikely. However, a negative result may not be used to exclude TB because false-negative results are exceedingly common.

63. Conditional Recommendation
They suggest that NAAT be performed, rather than not performed, on specimens collected from sites of suspected extrapulmonary TB. Remarks: A positive NAAT result can be used as evidence of extrapulmonary TB and guide decision making because false-positive results are unlikely. However, a negative NAAT result may not be used to exclude TB because false-negative results are exceedingly common. At present, NAAT testing on specimens other than sputum is an off-label use of the test.

64. Conditional Recommendation
They suggest that histological examination be performed, rather than not performed, on specimens collected from sites of suspected extrapulmonary TB. Remarks: Both positive and negative results should be interpreted in the context of the clinical scenario because neither false- positive nor false-negative results are

65. Strong Recommendation
They recommend one culture isolate from each mycobacterial culture-positive patient be submitted to a regional genotyping laboratory for genotyping.

66. Benefits of Genotyping
Genotyping is useful in detecting false-positive results due to confirming laboratory cross-contamination
Investigating outbreaks of TB (both detecting unsuspected outbreaks and confirming suspected outbreaks)
Evaluating contact investigations.
Determining whether new episodes of TB are due to reinfection or reactivation.

67. World TB Day Quizlet Smear, culture and PCR
You have a 15 year old young man from India who presents with parents with a 4 x 5 cm cervical lymph node. He also has intermittent fevers and a positive IGRA. You call ENT to biopsy the node. What tests on the specimen do you ask them to send?
Smear, culture and PCR

68. Summary

69. New Guidelines
Evidenced based recommendations that are based on both the likelihood of infection and risk for progression to disease
Facilitate an timely identification of TB and the appropriate treatment
Promote identification of genotype which aids public health in identifying and following (and hopefully containing) outbreaks

70. Now, go forth and lunch