1. Institute for Health Service Research for Healthcare Workers (CVcare)
TB in healthcare workers (HCW)
Albert Nienhaus

2. Leitmotif 1 WHO Guideline on Latent TB Infection (LTBI)
2 TB risk in HCWs
3 TST and IGRA in HCWs
4 Serial testing of HCW

3. Register for TB screening in HCWs
TB-Net for HCWs
Register for TB screening in HCWs
32 physicians contribute data to the register
Pre-employment screening
contact tracing and
repeated testing of HCWs from TB-wards
So far 4,200 HCWs included in the register
Register is financed by the compensation board for HCWs (Berufsgenossenschaft)

4. Additional sources of data for the presentation
I have the honour to collaborate with
José Torres Costa, University Clinics Porto, Portugal
Dominique Tripodi, University Clinics Nantes, France
Paul-Kenneth Gariepy, Hospital St Anne, Paris, France

5. LTBI
WHO 2015
Treatment of LTBI is key to TB elimination in low TB incidence countries

6. General considerations of the WHO working group
LTBI treatment might result in unwanted side effects
hepatitis
Benefit of treatment must be greater than potential harm
No general screening, no treatment of all LBTI cases
High risk group screening and treatment

7. Concept of high risk groups
LTBI prevalence
high
low
Screen and treat
Conditionally
screen and treat
Low prevalence,
Low progression risk
high
Progression risk
low

8. High risk groups A strong recommendation
people living with HIV,
adult and child contacts of pulmonary TB cases,
patients initiating anti-tumor necrosis factor (TNF) treatment,
patients receiving dialysis,
patients preparing for organ or haematologic transplantation,
patients with silicosis
contradicted by Ringshausen et al Plos one 2013 for German minors.
Testing and treatment of LTBI should be performed

9. High risk groups B conditional recommendation
prisoners (prison employees),
healthcare workers,
immigrants from high TB burden countries,
homeless persons,
illicit drug users
Testing and treatment of LTBI should be considered depending on national circumstances, recourses, regulations and priorities

10. Which immunologic test should be used following WHO
TST or IGRA
No recommendation
Populations with BCG vaccination or NTM exposure
not discussed
Reason for (missing) recommendation
Availability of test
(using either test is better than not testing at all)
(Remember: Recommendation for intermediate and high income countries / TB incidence < 100/100,000 countries)

11. Leitmotif WHO Guideline on Latent TB Infection (LTBI) TB risk in HCWs
TST and IGRA in HCWs
Serial testing of HCW

12. Relative Risk for active TB in HCW vs. general population
Low TB incidence
2.4 ( )
IntermediateTB incidence
2.5 ( )
High TB incidence
3.7 ( )
Baussano I et al. CDC 2011

13. a waiter from Bali was seen one time for throat problems
Active TB in a HCW
case
age
sex
IS6110-DNA-Fingerprint 1 2 25 68 m
Index
ENT-doctor
a waiter from Bali was seen one time for throat problems
3 weeks later, the waiter was diagnosed with TB
3 years later, the physician (ENT-doctor) developed TB
Hamburg Fingerprint-Study
Diel R et al Resp Research 2005;6:35

14. Hamburg Fingerprint Study 1997 - 2015
based on
TB registry in Germany
2,050 patient
41 HCW (2%)
cluster
825 (40.2%)
no cluster
1,125 (59.8%)
HCW in Cluster
22 (53.7%)
HCW no Cluster
19 (46.3%)
patient to HCW
N=12
29.4%
HCW to 2 patients
N=1
2.4%
HCW to family
N=1
2.4%
no transition
N=8
19.5% no
cluster
N=19
46.3%
unpublished data, courtesy R Diel, S Niemann

15. TB transmission from HCW to patients?
Surprisingly little published evidence
28 reports; transmission rate from HCW with TB to contact 1-5%
Schepisi et al 2015: Tuberculosis Transmission from Healthcare Workers to Patients and Co-workers: A Review Plos one 2015
A lot of contacts to be contacted
e.g. contact investigation around a healthcare worker (HCW) with infectious TB on a maternity ward in Atlanta in 2013
285 patients who interacted with the HCW
Sanderson et al.: J Am Med Inform Assoc Sep;22(5):

16. Risk of TB infection in HCW
Studies using population controls are based on TST
Increased risk is well established for low TB incidence, high income countries
Seidler et al. 2005; Boussano et al 2011
I am not aware of any study using population controls and IGRA
Comparison between HCWs with different probabilities of exposure using IGRA (TB-Net for HCWs)
OR 95%CI
Lab / Path
Geriatric care
Infection ward
Schablon et al Plos one 2014

17. What do we know about progression risk in HCWs?
latent TB infection (LTBI)
active TB
latent TB infection
preventive
treatment (INH)
early case detection, isolation and treatment
early case detection, isolation and treatment
If finding active TB is unlikely, you might want to find those who will eventually progress to active TB

18. Progression risk in HCW with positive immunologic test
IGRA -TST
1218
Hospital de São João, Porto
Torres Costa et al. JOMT 2011
IGRA+/TST+
371
IGRA+/THT+
371
IGRA-/TST+
532
IGRA-/THT+
532
IGRA+/TST- 26
IGRA+/THT- 26
IGRA-/TST-
289
IGRA-/THT-
289
active TB
8 (2.2%)
active TB
active TB
active TB
Progression
active TB
Progression TB
4 (1%)
Progression TB
This is below what WHO assumes: IGRA 5%, TST 3%

19. Different progression rates ?
in general population 12% Diel et al. AJRCCM 2011
Pooled estimate WHO 5%
in HCWs % Torres Costa et al. JOMT 2011
potential reasons
proportion of old infections in HCWs higher
progression in children higher than in adults
33% versus 10% in the German progression study
poverty
alcoholism
drug abuse
homelessness

20. Concept of high risk groups
LTBI prevalence
high
low
Screen and treat
Conditionally
screen and treat
HCW
Low prevalence,
Low progression risk
high
Progression risk
low

21. Leitmotif WHO Guideline on Latent TB Infection (LTBI) TB risk in HCWs
TST and IGRA in HCWs
Serial testing of HCW

22. TST or IGRA ? Remember: Diagnosis of LTBI
Positive immunologic test and active TB excluded by X-ray
TST + X-ray
TST + IGRA + X-ray
IGRA + X-ray

23. head to head IGRA und TST
Studien-kollektiv
IGRA+ /TST+
IGRA-/TST+
IGRA+ /TST-
IGRA-/TST-
Country N
N (%)
Germany
261
15 (5.7)
48 (18.4)
10 (3.8)
188 (72.4)
Portugal
1,218
371 (30.5)
532 (43,7)
26 (2.1)
289 (23.7)
France
148
23 (15.5)
74 (50.0)
5 (3.3)
46 (31.1)
All
1627
409 (25,1)
654 (40,2)
41 (2,5)
523 (32,1)
Nienhaus et al Pneumologie 2011
X-ray and
preventive chemotherapy spared

24. Effectiveness of TB screening in HCWs?
We know very little about the effectiveness
We have no data to tell us which strategy works best
Cost effectiveness studies of TB screening in HCWs show that screening is cost effective
Two reviews available
Nienhaus et al. JOMT 2011
Diel, Nienhaus Pharmaco-economics 2015
IGRA based screening in high risk group is cost-effective
The most recent and most convincing example I know comes from Portugal

25. TB screening in Portuguese HCWs
OSH department inaugurated in 2005
in 2006 – 2008
a total of 33 cases of active TB in HCWs
191 cases / 100,000 HCWs
Relative Risk (RR): 5.99 (95%CI )
incidence of TB in HCW decreased because of systematic screening and improved hygiene
Active TB in HCW ( year)
13 (2006) 14 (2007) 6 (2008) 5 (2009) 2 (2010) 0 (2011) 1
Torres Costa Eur Respir J 2009; 34:

26. TB prevention in healthcare
Early detection of cases
Isolation of smear positive cases
Effective treatment of cases
Mask for patients
Respirator for HCW
In addition
TB screening for HCW
The ensemble works, the contributions of the single players are unknown

27. Leitmotif WHO Guideline on Latent TB Infection (LTBI) TB risk in HCWs
TST and IGRA in HCWs
Serial testing of HCW

28. Should we repeat IGRA in serial testing of HCW?
Before the advent of IGRA
A positive TST was not repeated
Boosting, strong reaction
Avoid confusion
Once positive in TST,
X-ray in routine screening ever after
LTBI was considered a stable state (and its variability forgotten)
High reversion rate in IGRA
was a surprise
? reversers do not need X-ray? (This is a big advantage for those HCWs pertaining to repeated screening schemas)

29. LTBI is an unstable state
Active TB
Transient infection
8 weeks
Dormant state
Local reaction lung
TB granuloma (LTBI)
Low replication with T cell stimulation
TNFα control
Uncontrolled replication
Subclinical or clinical TB

30. When analyzing the same tube twice
Concordance of the results >98 %
but variation of the concentration (30 % of the mean)
For results close to the cut-off, this might cause problems,
otherwise this is no problem but a scientific challenge

31. Reversion and risk of LTBI
Specificity of test 95 %, sensitivity 100 %
Risk of LTBI 2 % % 50 %
Expected positive
Expected reversion >50% % <10%
Country US Germany South Africa

32. Reversion in TST and QFT
QFT positive 2,761 (52 %)
Reversion 4.3 – 5.7 %

33. Reversion in TST and QFT
QFT positive 2,761 (52 %)
Reversion – 5.7 %
TST positive 2,987 (56 %)
Reversion – 4.5 %

34. Risk factors for conversion of QFT in 3582 HCWs
INF-γ first QFT OR
95%CI
<0.1 IU/ml 1 --
0.1-<0.2 IU/ml
3.0
1.8 – 4.9
0.2-<0.35 IU/ml
7.5
4.7 – 12.1
Germany
Portugal
no influence of age and gender

35. Risk factors for reversion in 640 HCW
INF-γ first QFT OR
95%CI
0.35-<0.7 IU/ml
4.6
3.1 – 6.9
0.7-<1.0 IU/ml
1.5
1.0+ IU/ml 1 --
no influence of age and gender
HCWs with a reversion can go back into the IGRA screening pool

36. Do we need a borderline zone?
The data suggest to use a borderline zone
0.2 – 0.7 IU/ml
in groups with no recent exposure and low progression risk
Let‘s be careful in exposed groups

37. TB in Portuguese HCW 2 25.0 1 TB QFT results Total Negative
<0.2 IU/mL
Pos. borderline
0.35–<0.7 IU/mL
Positive
≥0.7 IU/mL n %
TB in history 16
28.1 15
26.3 26
45.6 57
2.0
Active TB at screening - 2
25.0 6
75.0 8
0.3
Progression to active TB 1 3 4
0.1
No TB
1,764
62.7
323
11.5
728
25.9
2,815
97.6
All
1,780
61.7
341
11.8
763
26.5
2,884
100.0
Nienhaus and Torres Costa JOMT 2013