Anti-TNF, Immunosuppression and Renal Disease: Approaches in TB

Anti-TNF, Immunosuppression and Renal Disease: Approaches in TB Dr Heather Milburn Consultant Respiratory Physician Guy’s & St Thomas’ NHS Foundation Trust READER IN Respiratory Medicine KING’S College London

Relative risk of developing active TB (Nice Guidelines, 2006/2011)

Clinical Condition

Relative Risk

Diabetes mellitus Solid organ transplantation

2-4 20-74

Silicosis 30 Chronic renal failure/haemodialysis 10-25.3 Gastrectomy Contact smear +ve TB

2.5 5-10

HIV

10

Anti-TNF therapy Corticosteroids, MMF, tacrolimus, ciclosporin, aza, mtx, rituximab…..

5 ?

Difficulties in Management of TB & LTBI in Renal Disease • Risk: ethinic minorities inc risk both TB & CKD

• Screening: when? How? skin anergy; IGRA tests – evaluation.

• Diagnosis: unusual presentations • Treatment: timing; dosage; drug interactions.

Renal Disease – TB Risk • Chronic Kidney Disease - Acqu’d i/d state - Functional abnorm N, T&B lympho, monos, NK cells; vitamin D deficiency - Risk 31.4 in China, ?UK • Maintenance Haemodialysis - Risk 10-25x (NICE 2006) • Transplant - Risk 100-400x (Europe & USA; ISC ?higher) - NICE 2006 overall relative risk x37

Incidence of TB - CKD • TB incidence UK 15/100,000; London 44.4/100,000 • Dialysis 1,187/100,000 (Moore et al 2002) No. of cases/100,000

1400 1200 1000 800 600 400 200

CAPD

Haemodialysis

Functioning Transplant

Total Transplants

General UK Population

London

0

Palchaudhuri et al 2011

Uraemic Milieu Intracellular Ca++ Zn deficiency

Malnutrition – low albumin

Fe overload

Uraemic toxins – guanidines, polyamines

neutrophil

Myeloperoxidase O2 radicals bacterial killing bacterial virulence

Uraemic milieu

Renal replacement therapy

Vit D deficiency C’ activation IL1b IL6 Monocyte/APC

Chronic inflammation

TNFa

IL12 costimulation IL6/IL10 imbalance

T cell

IL6

TH1

differentiation

TH2

IL4 IFNg

Cellular immune response

B cell

Humoral immune response

Renal Disease – LTBI & Prophylaxis • Who? - All uraemic patients? - Only those with particular risk? • When? - CKD? - On dialysis? - Pre-transplant? - Post-transplant? • How? - TST? - IGRA? • What? - 6/12 H - 3/12 RH (drug interactions) - 4-6/12 R (drug interactions)

Renal Disease – Method of Screening • Pre-transplant • TST – Anergy 30-50% Drugs – pred, aza, 6-MCP, mtx, cycloph, mycophenolate, ciclosp, tacrolimus • Interferon-g tests – evaluation? • CXR

Bumbacea et al. Eur Respir J 2012;40:990-1013

IGRAs in Immunosuppression CKD Systematic Review of 30 studies (47): • Predominantly HD • Countries with low-mod TB prevalence • 9 compared IGRAs with TST, 17 TST only, 4 other tests. • cf +ve TST, +ve ELISA more strongly assoc with radiol evidence past TB (OR 4.29, CI 1.83-10.3, p=0.001) and contact with aTB (OR 3.36, CI 1.61-7.01, p=0.001) • cf –ve TST, -ve ELISA more strongly assoc with BCG (OR 0.30, CI 0.14-0.63, p=0.002) • Insufficient data to compare ELISPOT with TST or ELISA • ELISA more strongly assoc with risk factors for LTBI in CKD than TST (Rogerson et al., Am J Kidney Dis 2013)

Study design

Data set consisting of • Mendel Mantoux skin-test • T-SPOT.TB • QuantiFERON-TB Gold In-Tube

Clinical data • TB risk factors • Level of immunosuppression TBNET

Percentage of positive results

Similar percentages of positive test results in all assays

CRF

40

30

26.3%

26.7%

27.1%

all 5 years of dialysis

20

10 0

TBNET

Patients with chronic renal failure

Percentage of positive results

Similar percentages of positive test results in all assays

CRF

40

30

all 5 years of dialysis

20

10

TBNET

0

Patients with chronic renal failure

Agreement between the tests K=0.3 2

neg

pos

K=0.2 8

neg

CRF

pos

neg

158 (60.3%)

35 (13.4%)

neg

155 (59.2%)

38 (14.5%)

pos

34 (13.0%)

35 (13.4%)

pos

36 (13.7%)

33 (12.6%)

K=0.5 2

neg

pos

TBNET

neg

167 (63.7%)

25 (9.5%)

pos

24 (9.2%)

46 (17.6%)

CRF No association with TB exposure crude

TBNET

age, sex, duration of dialysis

OR

95% CI

OR

95% CI

1.2

0.6-2.2

1.1

0.6-2.3

1.3

0.7-2.3

1.2

0.6-2.3

1.2

0.6-2.5

1.3

0.6-2.6

BTS Recommendations 2010 • Screening for LTBI - Method: Use IGRA with or without TST

• Who to screen: Pre-transplant Contacts

• Chemoprophylaxis: 6H if post transplant 3RH if pre transplant 4R if pre transplant

Drug Recommendations: Chemoprophylaxis • H & R - normal doses in CKD. • Long term use of isoniazid is not recommended. • No evidence for prolonged chemoprophylaxis with any of above. • No evidence for lower doses - lower peak levels and drug resistance. Guidelines for management of TB & LTBI in CKD;Thorax 2010:65:559-70

Active TB Routine Assessment: • History – prev TB, Rx & time, recent contact • Chronic cough, wt loss, sweats – CXR • Sputum, ind sputum, FOB, EBUS Presentation: • Not always classic • Extra pulmonary common – 30-50%; peritoneal Investigation: • Active TB suspected –fluid or tissue for culture & sensitivity testing; histology • Active pulm disease – isolate in negative pressure room • Notify • INVOLVE CHEST PHYSICIANS

40yr old white M Peritoneal dialysis 1yr Abdom pain, Cloudy dialysate, No cough T 38, WCC 5.4, N 4.4, Ly 0.8, CXR unremarkable Blood cultures –ve, MC&S of dialysate –ve From Latvia, UK 1yr Antibiotics 1/52 No improvement Further specimens neg Change antibiotics No improvement Abdo US – nodes and omental thickening Biopsy – granulomata, no AFB seen, grew H resistant TB

Pharmacokinetics & Toxicity of first-line drugs in CKD • H: metabolised by liver - neurotoxicity – give pyridoxine - neuropsychiatric disturbance - ototoxicity – rare and can occur in CKD • R: metabolised by liver - no signif increase tox • Z: metabolised by liver - uric acid retention – gout • E: 80% excreted unchanged by kidneys - ocular toxicity dose dependent - increased efficacy normal dose less often

Treatment aTB 47yr old Black African, HD, sm+ PTB, dry wt 68kg Management? Not on open HD unit! Medication: Rifater 6 daily Ethambutol 600mg daily

Renal Disease - Treatment CKD Stage 1 normal function but structural abnormality CKD Stage 2 Cr Cl 60-90mls/min; Stage 3 30-60mls/min; Stage 4 15-30mls.min; Stage 5