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

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

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)

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

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

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

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

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

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

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)

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

Relative Risk for active TB in HCW vs. general population Low TB incidence 2.4 (1.2-3.6) IntermediateTB incidence 2.5 (1.1-3.8) High TB incidence 3.7 (2.4-3.5) Baussano I et al. CDC 2011

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

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

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. 2015 Sep;22(5):1089-93

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 2.35 1.4-3.9 Geriatric care 1.98 1.2-3.3 Infection ward 1.76 1.04-3.0 Schablon et al Plos one 2014

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

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%

Different progression rates ? in general population 12% Diel et al. AJRCCM 2011 Pooled estimate WHO 5% in HCWs 1% 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

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

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

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

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

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

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 4.2-8.5) 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: 1423-1428

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

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

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)

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

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

Reversion and risk of LTBI Specificity of test 95 %, sensitivity 100 % Risk of LTBI 2 % 10 % 50 % Expected positive 2+5 10+4.5 50+5 Expected reversion >50% 30% <10% Country US Germany South Africa

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

Reversion in TST and QFT QFT positive 2,761 (52 %) Reversion 4.3 – 5.7 % TST positive 2,987 (56 %) Reversion 3.8 – 4.5 %

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

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 0.8 -2.6 1.0+ IU/ml 1 -- no influence of age and gender HCWs with a reversion can go back into the IGRA screening pool

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

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