Open access Research Screening and prevention for …hasan t, etal Open 20188e022445 doi101136bmjopen2018022445 1 Open access Screening and prevention for latent tuberculosis in immunosuppressed

1Hasan T, et al. BMJ Open 2018;8:e022445. doi:10.1136/bmjopen-2018-022445

Open access

Screening and prevention for latent tuberculosis in immunosuppressed patients at risk for tuberculosis: a systematic review of clinical practice guidelines

Tasnim Hasan,1 Eric Au,2 Sharon Chen,1,3 Allison Tong,4,5 Germaine Wong2,5

To cite: Hasan T, Au E, Chen S, et al. Screening and prevention for latent tuberculosis in immunosuppressed patients at risk for tuberculosis: a systematic review of clinical practice guidelines. BMJ Open 2018;8:e022445. doi:10.1136/bmjopen-2018-022445

► Prepublication history and additional material for this paper are available online. To view these files, please visit the journal online (http:// dx. doi. org/ 10. 1136/ bmjopen- 2018- 022445).

Received 18 February 2018Revised 15 July 2018Accepted 25 July 2018

For numbered affiliations see end of article.

Correspondence toDr Tasnim Hasan; tasnim. hn@ gmail. com

Research

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

AbstrACtObjective Immunosuppressed individuals are at a high risk of latent tuberculosis infection (LTBI) and clinical practice guidelines for the screening and management of LTBI in at-risk patients have been developed. We assessed the scope, quality and consistency of clinical practice guidelines on screening for LTBI and the prevention of tuberculosis infection (TB) in high-risk patient populations.Design We conducted a systematic review of clinical practice guidelines. Methodological quality of these guidelines was assessed using the Appraisal of Guidelines for Research and Education (AGREE) II instrument. Textual synthesis was used to summarise and compare the recommendations.Data sources Electronic databases (MEDLINE, EMBASE, PsycINFO) and guideline registries were searched from inception to December 2017.results Thirty-eight guidelines were included. Nineteen focused on patients receiving medical immunosuppression, seven on transplantation, three on patients with HIV and nine were generalised across all at risk populations. Most guidelines (n=32, 84%) used a systematic approach to identify and appraise the evidence. The methodological quality of the guidelines varied with the overall mean AGREE II scores ranging from 35% to 80%. Guidelines performed poorly in terms of editorial independence (average score 35%, range 0%–92%); however, most were robust in defining their scope and purpose (average score 80%, range 56%–100%). Guidelines recommended either or both the tuberculin skin test and the interferon gamma release assay for screening. Treatment of LTBI with isoniazid was consistently recommended.Conclusion Clinical practice guidelines on LTBI vary in quality and scope. The recommendations for screening varied across guidelines, while recommendations for treatment were largely consistent. Improving the consistency and quality of guidelines may help to optimise the screening and management of LTBI for improved patient outcomes.

IntrODuCtIOn Immunosuppression increases the risk of reactivation of prior infection with

Mycobacterium tuberculosis leading to tubercu-losis (TB) disease. In high-income countries, the baseline risk of reactivation of latent TB infection (LTBI) varies between 6 and 20 per 100 000 persons per year.1 2 The magnitude of the risk of TB reactivation among those who are immunosuppressed varies depending on the types of immunosuppression. The excess risk is highest among solid organ transplant recipients, particularly in lung (15-fold higher compared with the general population)3 and stem cell transplant recipients (6–10-fold higher),4 followed by recipients of tumour necrosis factor (TNF) antagonists (5–7-fold higher).5–8 The risk of TB reactivation in patients with HIV infection is 3–20 times higher than the general population9 10 and causes up to 25% of deaths in these patients.9

Early detection of LTBI through screening of patients at increased risk for TB may provide a window of opportunity for inter-ventions such as treatment to prevent the development of active TB. Screening often involves the use of the commercially avail-able tuberculin skin test (TST) and an inter-feron gamma release assay (IGRA). IGRAs include the QuantiFERON-TB Gold Plus (Cellestis, Australia) and the T-SPOT test

strengths and limitations of this study

► This study systematically reviewed published clinical practice guidelines for screening and management of latent tuberculosis infection in immunosup-pressed patients.

► We used the Appraisal of Guidelines for Research and Evaluation II instrument, an internationally val-idated tool, to assess the quality of the guidelines.

► We included 38 guidelines and 11 non-English guidelines were excluded, with only few guidelines published in low-resource settings.

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2 Hasan T, et al. BMJ Open 2018;8:e022445. doi:10.1136/bmjopen-2018-022445

Open access

(Oxford Immunotec, UK). However, there are poten-tial drawbacks associated with screening. False negative results (2.8% in one setting11) with attendant false assur-ance may lead to late or missed diagnoses and delayed treatment. Conversely, false positive results may lead to unnecessary and inappropriate investigations which may be harmful.12 There is also a lack of a valid and accurate reference standard for diagnosing LTBI in immunosup-pressed populations, rendering the true test performance characteristics of IGRA difficult to ascertain.

To advise health practitioners, clinical practice guide-lines have provided evidence-based recommendations that inform practitioner and patient decisions about appropriate healthcare for specific clinical circum-stances.13 As such, guidelines on screening for LTBI and treatment in at-risk populations have been developed in various healthcare settings. However, it is unclear if these recommendations may be generalisable to others or if there is variability. Therefore, this review aims to assess and compare the rationale, scope, quality and consistency of clinical practice guidelines and consensus statements for the screening of LTBI, as well as for treatment against LTBI in immunosuppressed individuals.

MethODsselection criteriaEvidence-based clinical practice guidelines and consensus statements on screening for LTBI and treatment for LTBI in immunosuppressed individuals published in English were eligible for inclusion. Patients who were medically immunocompromised (including chemotherapy, disease modifying agents and biological therapy), had received a solid organ or stem cell transplant or HIV positive were included. Draft or unpublished guidelines, conference or discussion papers, opinions and guidelines and consensus statements replaced by updated and/or revised recom-mendations were excluded.

Literature searchWe searched MEDLINE, Embase and PsycINFO from database inception to December 2017. Medical Subject Heading (MeSH) terms and text words for ‘tuberculosis’, ‘immunosuppressed’ and ‘immunocompromised’ were combined with terms relating to clinical practice guide-lines and consensus statements (online supplementary appendix 1). Clinical guideline registries and reference lists were searched for additional clinical practice guide-lines. Titles and abstracts were reviewed by two authors (TH and EA), and those which did not meet the inclusion criteria were excluded. Full text versions of potentially relevant guidelines or consensus statements were exam-ined for eligibility.

Appraisal of guidelines and consensus statementsThe methodological quality was assessed independently by TH and EA, using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument.14

AGREE II is an internationally validated, rigorously devel-oped 23-item tool used to evaluate independent domains of guideline development including: scope and purpose, stakeholder involvement, rigour of development, clarity and presentation, applicability and editorial indepen-dence. Each item was rated on a seven-point scale ranging from strongly disagree (score 1) to strongly agree (score 7). The domain score was obtained by summing all scores of the individual items per domain and then standard-ising the total as a percentage of the maximum possible score for that domain:

obtained score−minimum possible score

maximum possible score−minimum possible score

The minimum possible domain score would be the number of questions multiplied by the number of appraisers, multiplied by 1 (strongly disagree). The maximum possible domain score is the number of ques-tions multiplied by the number of appraisers, multi-plied by 7 (strongly agree). The AGREE scores were rated independently for each guideline by TH/EA and a quadratic weighted kappa (κ) score for each guideline and across all guidelines were calculated as a measure of inter-rater agreement. An overall weighted kappa was also calculated across all guidelines.

textual synthesisAll text from each guideline were entered into the Hyper-RESEARCH software (ResearchWare 2011, V.3.0.3, Randolph, Massachusetts, USA) for storing, coding and searching textual data. Data were categorised by subheadings based on immunosuppression modality and by screening and treatment methods. Subse-quently, we conducted a textual descriptive synthesis to analyse the content, consistency and evidence base of the recommendations.

Patient and public involvementThere was no patient or public involvement in this study.

resuLtsCharacteristics of clinical practice guidelinesWe included 38 guidelines (figure 1) published from 2002 to 2017. These guidelines focused on medical immunosuppression (19 guidelines),1 15–32 solid organ and stem cell transplantation (seven guidelines)3 33–38 and in HIV settings (three guidelines).9 39 40 Nine were general guidelines which were not specific to a partic-ular patient group and covered the detection of LTBI and its management.10 41–46 These guidelines were published across 16 different countries from regions including North America, Western Europe, Asia, Australia and South Africa. A summary of the guideline characteristics is provided in table 1.

Of the guidelines that discussed medical immunosup-pression, nine provided recommendations for treatment across various medical specialties including derma-tology, rheumatology, gastroenterology and respiratory



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medicine.15 16 18 21 24 26 28 29 31 Four were specific to patients with rheumatoid arthritis,20 23 25 27 of which one focused only on patients receiving infliximab,23 while two guide-lines were specific to patients with psoriasis.18 30 One guideline focused on patients with rheumatological or gastroenterological disease.15 There were specific

guidelines addressing inflammatory joint disease,19 rheu-matological disease1 and autoimmune bullous diseases.22 One guideline discussed patients at risk due to metho-trexate therapy.32 Of the transplantation guidelines, two guidelines were for kidney transplantation,34 36 one for stem cell transplantation,38 one for both solid organ and

Figure 1 Database search strategy The medical databases EMBASE, PsychINFO and Medline were searched for articles relevant to tuberculosis in an immunosuppressed setting, using the search strategy described in online supplementary appendix 1. A total of 9467 articles were found and compiled into the EndNote software (Clarivate Analytics 2017, V.X7), of which 1130 articles were duplicate articles. From the remaining articles, 6121 articles were excluded by abstract review, primarily because they were irrelevant. A further 2056 articles were removed during a second review of titles and abstracts. A total of 160 articles were reviewed in full of which 122 were excluded as they did not fulfil guideline or relevance criteria. A total of 38 articles were included in our final review.



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from

at

leas

t on

e w

ell d

esig

ned

non

-RC

T, c

ohor

t or

cas

e co

ntro

l or

non-

cont

rolle

d e

xper

imen

tal s

tud

y w

ith n

on-c

oncl

usiv

e re

sults

, III:

Exp

ert

opin

ion

bas

ed o

n cl

inic

al e

xper

ienc

e,

des

crip

tive

stud

ies,

rep

ort

from

exp

ert

pan

el.

†A: S

olid

evi

den

ce o

f clin

ical

ben

efit,

B: S

olid

or

mod

erat

ely

solid

evi

den

ce fo

r ef

ficac

y, b

ut c

linic

al b

enefi

t is

lim

ited

, C: I

nsuf

ficie

nt e

vid

ence

for

effic

acy,

D: M

oder

atel

y so

lid e

vid

ence

for

lack

of e

ffica

cy, E

: Str

ong

evid

ence

for

lack

of e

ffica

cy.

‡I: O

ne o

r m

ore

RC

T w

ith c

linic

al o

utco

mes

and

/or

valid

ated

lab

orat

ory

end

poi

nts,

II: O

ne o

r m

ore

wel

l-d

esig

ned

, non

-ran

dom

ised

tria

ls o

r ob

serv

atio

nal c

ohor

t st

udie

s w

ith lo

ng-t

erm

clin

ical

out

com

es II

I: E

xper

t op

inio

n.§A

: Str

ong

reco

mm

end

atio

n fo

r th

e st

atem

ent,

B: M

oder

ate

reco

mm

end

atio

n fo

r th

e st

atem

ent,

C: O

ptio

nal r

ecom

men

dat

ion

for

the

stat

emen

t.¶

GR

AD

E—

Hig

h: F

urth

er r

esea

rch

is v

ery

unlik

ely

to c

hang

e ou

r co

nfid

ence

in t

he e

stim

ate

of e

ffect

. Mod

erat

e; F

urth

er r

esea

rch

is li

kely

to

have

an

imp

orta

nt im

pac

t on

our

con

fiden

ce in

the

effe

ct. L

ow: F

urth

er r

esea

rch

is v

ery

likel

y to

hav

e an

imp

act

on

the

estim

ate

of e

ffect

and

is li

kely

to

chan

ge t

he e

stim

ate.

Ver

y lo

w: A

ny e

stim

ate

of e

ffect

is v

ery

unce

rtai

n.**

(1) A

str

ong

reco

mm

end

atio

n is

one

for

whi

ch t

he P

anel

was

con

fiden

t th

at t

he d

esira

ble

effe

cts

of a

dhe

renc

e to

the

rec

omm

end

atio

n ou

twei

gh t

he u

ndes

irab

le e

ffect

s. T

his

coul

d b

e ei

ther

in fa

vour

of o

r ag

ains

t an

inte

rven

tion.

(2) A

con

diti

onal

re

com

men

dat

ion

is o

ne fo

r w

hich

the

Pan

el c

oncl

uded

tha

t th

e d

esira

ble

effe

cts

of a

dhe

renc

e to

the

rec

omm

end

atio

n p

rob

ably

out

wei

gh t

he u

ndes

irab

le e

ffect

s, b

ut t

he P

anel

was

not

con

fiden

t ab

out

thes

e tr

ade-

offs

. Rea

sons

for

not

bei

ng c

onfid

ent

incl

uded

: ab

senc

e of

hig

h-q

ualit

y ev

iden

ce (d

ata

to s

upp

ort

the

reco

mm

end

atio

n ar

e sc

ant);

pre

senc

e of

imp

reci

se e

stim

ates

of b

enefi

ts o

r ha

rms

(new

evi

den

ce m

ay r

esul

t in

cha

ngin

g th

e b

alan

ce o

f ris

k to

ben

efit);

unc

erta

inty

or

varia

tion

rega

rdin

g ho

w

diff

eren

t in

div

idua

ls v

alue

the

out

com

es (o

nly

app

licab

le t

o a

spec

ific

grou

p, p

opul

atio

n or

set

ting)

; sm

all b

enefi

ts a

nd b

enefi

ts t

hat

may

not

be

wor

th t

he c

osts

(inc

lud

ing

the

cost

s of

imp

lem

entin

g th

e re

com

men

dat

ion)

.

Tab

le 1

C

ontin

ued

Con

tinue

d



jopen.bmj.com

/B

MJ O


eptember 2018. D

ownloaded from



Open access

Gui

del

ines

Fund

ing

bo

dy

Co

untr

yP

op

ulat

ion

Targ

et u

sers

Wri

ters

Evi

den

ce

bas

eE

vid

ence

leve

lG

rad

ing

Gui

del

ine

revi

ewU

pd

ate

††IA

: Evi

den

ce in

clud

es e

vid

ence

from

met

a-an

alys

is o

f ran

dom

ised

con

trol

led

tria

ls; I

B: E

vid

ence

incl

udes

evi

den

ce fr

om a

t le

ast

one

rand

omis

ed c

ontr

olle

d t

rial;

IIA: E

vid

ence

incl

udes

evi

den

ce fr

om a

t le

ast

one

cont

rolle

d s

tud

y w

ithou

t ra

ndom

isat

ion;

IIB

: Evi

den

ce in

clud

es e

vid

ence

from

at

leas

t on

e ot

her

typ

e of

qua

si-e

xper

imen

tal s

tud

y; II

I: E

vid

ence

incl

udes

evi

den

ce fr

om n

on-e

xper

imen

tal d

escr

iptiv

e st

udie

s, s

uch

as c

omp

arat

ive

stud

ies,

cor

rela

tion

stud

ies

and

cas

e-co

ntro

l stu

die

s; IV

: Evi

den

ce

incl

udes

evi

den

ce fr

om e

xper

t co

mm

ittee

rep

orts

or

opin

ions

or

clin

ical

exp

erie

nce

of r

esp

ecte

d a

utho

ritie

s or

bot

h.‡‡

Evi

den

ce le

vel d

efini

tions

not

sp

ecifi

ed.

§§Le

vel 1

: An

RC

T th

at d

emon

stra

tes

a st

atis

tical

ly s

igni

fican

t d

iffer

ence

in a

t le

st o

ne m

ajor

out

com

e or

if t

he d

iffer

ence

is n

ot s

tatis

tical

ly s

igni

fican

t, a

n R

CT

of a

deq

uate

sam

ple

siz

e to

exc

lud

e 25

% d

iffer

ence

in r

elat

ive

risk

with

80%

pow

er, g

iven

the

ob

serv

ed r

esul

ts. L

evel

2: A

n R

CT

that

doe

s no

t m

eet

the

Leve

l 1 c

riter

ia. L

evel

3: A

non

-ran

dom

ised

tria

l with

con

curr

ent

cont

rols

sel

ecte

d b

y so

me

syst

emat

ic m

etho

d. L

evel

4: B

efor

e-af

ter

stud

y or

cas

e se

ries

(at

leas

t 10

pat

ient

s) w

ith h

isto

rical

con

trol

s or

con

trol

s d

raw

n fr

om o

ther

stu

die

s. L

evel

5: C

ase

serie

s (a

t le

ast

10 p

atie

nts)

with

out

cont

rols

. Exp

erts

’ op

inio

n an

d c

linic

al e

xper

ienc

e ar

e in

clud

ed.

¶¶

Leve

l 1: E

valu

atio

n of

evi

den

ce s

atis

fies

all o

f the

follo

win

g cr

iteria

: (1)

effe

ctiv

e tr

eatm

ent

is d

ocum

ente

d in

RC

Ts t

hat

obse

rve

effe

cts

on c

linic

al o

utco

mes

; (2)

the

con

diti

on b

eing

scr

eene

d h

as lo

cal p

reva

lenc

e d

ata;

(3) t

he s

cree

ning

tes

t is

val

idat

ed

and

(4) t

he c

ost-

effe

ctiv

enes

s of

the

scr

eeni

ng t

est,

as

wel

l as

trea

tmen

t fo

r th

e d

isea

se h

ave

bee

n ev

alua

ted

. Lev

el 2

: Eva

luat

ion

of e

vid

ence

sat

isfie

s #1

but

not

all

of #

2, #

3 an

d #

4. L

evel

3: E

valu

atio

n of

evi

den

ce s

atis

fies

#2, #

3 or

#4

but

not

#1.

Lev

el

4: E

valu

atio

n of

evi

den

ce s

atis

fies

none

of t

he c

riter

ia.

***R

ecom

men

dat

ions

acc

ord

ing

to c

ateg

orie

s of

str

engt

h: (A

) Goo

d e

vid

ence

to

sup

por

t th

e re

com

men

dat

ion,

(B) m

oder

ate

evid

ence

to

sup

por

t th

e re

com

men

dat

ion,

(C) p

oor

evid

ence

tha

t d

oes

not

enab

le t

he r

ecom

men

dat

ion

to b

e ei

ther

sup

por

ted

or

reje

cted

. Rec

omm

end

atio

ns a

ccor

din

g to

the

sci

entifi

c q

ualit

y. G

rad

e I:

Rec

omm

end

atio

n b

ased

on

at le

ast

one

wel

l-d

esig

ned

, con

trol

led

, RC

T. G

rad

e II:

Rec

omm

end

atio

n b

ased

on

at le

ast

one

wel

l-d

esig

ned

, but

not

RC

T, c

ohor

t st

udie

s, m

ultip

le t

ime-

serie

s st

udie

s or

ver

y ev

iden

t re

sults

in u

ncon

trol

led

tria

ls. G

rad

e III

: Rec

omm

end

atio

n b

ased

on

the

opin

ion

of e

xper

ts, d

escr

iptiv

e st

udie

s or

clin

ical

exp

erie

nce.

†††

Cat

egor

y A

: At

leas

t on

e R

CT

or m

eta-

anal

yses

of R

CTs

or

revi

ews

if th

ese

cont

ain

cate

gory

A r

efer

ence

s. C

ateg

ory

B: A

t le

ast

one

cont

rolle

d t

rial w

ithou

t ra

ndom

isat

ion

or a

t le

ast

one

othe

r ty

pe

of e

xper

imen

tal s

tud

y or

ext

rap

olat

ed

reco

mm

end

atio

ns fr

om R

CTs

or

met

a-an

alys

es. C

ateg

ory

C: N

on-e

xper

imen

tal d

escr

iptiv

e st

udie

s, s

uch

as c

omp

arat

ive

stud

ies,

cor

rela

tiona

l stu

die

s an

d c

ase-

cont

rol s

tud

ies,

whi

ch a

re e

xtra

pol

ated

from

RC

Ts, n

on-r

and

omis

ed c

ontr

olle

d s

tud

ies

or o

ther

ex

per

imen

tal s

tud

ies.

Cat

egor

y D

: Exp

ert

com

mitt

ee r

epor

ts o

r op

inio

ns o

r cl

inic

al e

xper

ienc

e of

res

pec

ted

aut

horit

ies.

Als

o in

clud

es a

ll ab

stra

cts.

‡‡‡I

: Ran

dom

ised

, con

trol

led

clin

ical

tria

ls (t

hera

peu

tic o

r d

iagn

ostic

) and

met

a-an

alys

es o

f ran

dom

ised

, con

trol

led

clin

ical

tria

ls o

r sy

stem

atic

rev

iew

s. II

: Pro

spec

tive

and

con

trol

led

but

non

-ran

dom

ised

inve

stig

atio

ns (c

ohor

t st

udie

s); d

iagn

ostic

tes

ting

eval

uate

d b

y d

irect

met

hod

s. II

I: S

tud

ies

that

are

con

trol

led

but

not

pro

spec

tive

(cas

e-co

ntro

l stu

die

s); d

iagn

ostic

tes

ting

eval

uate

d b

y in

dire

ct m

etho

ds.

IV: D

escr

iptiv

e st

udie

s, e

xper

t op

inio

ns a

nd n

arra

tive

revi

ews.

§§§(

A) r

and

omis

ed, c

ontr

olle

d c

linic

al t

rials

(the

rap

eutic

or

dia

gnos

tic) a

nd m

eta-

anal

yses

of r

and

omis

ed, c

ontr

olle

d c

linic

al t

rials

or

syst

emat

ic r

evie

ws.

(B) P

rosp

ectiv

e an

d c

ontr

olle

d b

ut n

onra

ndom

ised

inve

stig

atio

ns (c

ohor

t st

udie

s); d

iagn

ostic

tes

ting

eval

uate

d b

y d

irect

met

hod

s, O

R S

tud

ies

that

are

con

trol

led

but

not

pro

spec

tive

(cas

e-co

ntro

l stu

die

s); d

iagn

ostic

tes

ting

eval

uate

d b

y in

dire

ct m

etho

ds.

(C) D

escr

iptiv

e st

udie

s, e

xper

t op

inio

ns a

nd n

arra

tive

revi

ews.

¶¶

¶1+

+: H

igh

qua

lity

met

a-an

alys

es, s

yste

mat

ic r

evie

ws

of R

CTs

or

RC

Ts w

ith a

ver

y lo

w r

isk

of b

ias.

1+

: Wel

l con

duc

ted

met

a-an

alys

es, s

yste

mat

ic r

evie

ws

of R

CTs

or

RC

Ts w

ith a

low

ris

k of

bia

s. 1

2: M

eta-

anal

yses

, sys

tem

atic

rev

iew

s of

RC

Ts o

r R

CTs

w

ith a

hig

h ris

k of

bia

s. 2

++

: Hig

h-q

ualit

y sy

stem

atic

rev

iew

s of

cas

e-co

ntro

l or

coho

rt s

tud

ies.

Hig

h-q

ualit

y ca

se-c

ontr

ol o

r co

hort

stu

die

s w

ith a

ver

y lo

w r

isk

of c

onfo

und

ing,

bia

s or

cha

nce

and

a h

igh

pro

bab

ility

tha

t th

e re

latio

nshi

p is

cau

sal.

2+: W

ell-

cond

ucte

d c

ase-

cont

rol o

r co

hort

stu

die

s w

ith a

low

ris

k of

con

foun

din

g, b

ias

or c

hanc

e an

d a

mod

erat

e p

rob

abili

ty t

hat

the

rela

tions

hip

is c

ausa

l. 22

: Cas

e-co

ntro

l or

coho

rt s

tud

ies

with

a h

igh

risk

of c

onfo

und

ing,

bia

s or

cha

nce

and

a s

igni

fican

t ris

k th

at

the

rela

tions

hip

is n

ot c

ausa

l. 3:

Non

-ana

lytic

al s

tud

ies

(eg,

cas

e re

por

ts, c

ase

serie

s). 4

: Exp

ert

opin

ion.

****

(A) A

t le

ast

one

met

a-an

alys

is, s

yste

mat

ic r

evie

w, o

r R

CT

rate

d a

s 1+

+ a

nd d

irect

ly a

pp

licab

le t

o th

e ta

rget

pop

ulat

ion

or a

sys

tem

atic

rev

iew

of R

CTs

or

a b

ody

of e

vid

ence

con

sist

ing

prin

cip

ally

of s

tud

ies

rate

d a

s 1+

dire

ctly

ap

plic

able

to

the

targ

et

pop

ulat

ion

and

dem

onst

ratin

g ov

eral

l con

sist

ency

of r

esul

ts. (

B) A

bod

y of

evi

den

ce in

clud

ing

stud

ies

rate

d a

s 2+

+ d

irect

ly a

pp

licab

le t

o th

e ta

rget

pop

ulat

ion

and

dem

onst

ratin

g ov

eral

l con

sist

ency

of r

esul

ts o

r ex

trap

olat

ed e

vid

ence

from

stu

die

s ra

ted

as

1+

+ o

r 1+

. (C

) A b

ody

of e

vid

ence

incl

udin

g st

udie

s ra

ted

as

2+ d

irect

ly a

pp

licab

le t

o th

e ta

rget

pop

ulat

ion

and

dem

onst

ratin

g ov

eral

l con

sist

ency

of r

esul

ts o

r ex

trap

olat

ed e

vid

ence

from

stu

die

s ra

ted

as

2+. (

D) E

vid

ence

leve

l 3 o

r 4

or e

xtra

pol

ated

ev

iden

ce fr

om s

tud

ies

rate

d a

s 2+

.††

††S

tron

g re

com

men

dat

ion

for

use

of a

n in

terv

entio

n: B

enefi

ts o

f the

inte

rven

tion

outw

eigh

the

ris

ks; m

ost

pat

ient

s w

ould

cho

ose

the

inte

rven

tion

whi

le o

nly

a sm

all p

rop

ortio

n w

ould

not

; for

clin

icia

ns, m

ost

of t

heir

pat

ient

s w

ould

rec

eive

the

inte

rven

tion;

fo

r p

olic

y m

aker

s, it

wou

ld b

e a

usef

ul p

erfo

rman

ce in

dic

ator

. Wea

k re

com

men

dat

ion

for

the

use

of a

n in

terv

entio

n: R

isks

and

ben

efits

of t

he in

terv

entio

n ar

e fin

ely

bal

ance

d; m

any

pat

ient

s w

ould

cho

ose

the

inte

rven

tion

but

man

y w

ould

not

; clin

icia

ns

wou

ld n

eed

to

cons

ider

the

pro

s an

d c

ons

for

the

pat

ient

in t

he c

onte

xt o

f the

evi

den

ce; f

or p

olic

y m

aker

s, it

wou

ld b

e a

poo

r p

erfo

rman

ce in

dic

ator

whe

re v

aria

bili

ty in

pra

ctic

e is

exp

ecte

d. N

o re

com

men

dat

ion:

Insu

ffici

ent

evid

ence

to

sup

por

t an

y re

com

men

dat

ion.

Str

ong

reco

mm

end

atio

n ag

ains

t th

e us

e of

an

inte

rven

tion:

Ris

ks o

f the

inte

rven

tion

outw

eigh

the

ben

efits

; mos

t p

atie

nts

wou

ld n

ot c

hoos

e th

e in

terv

entio

n w

hile

onl

y a

smal

l pro

por

tion

wou

ld; f

or c

linic

ians

, mos

t of

the

ir p

atie

nts

wou

ld

not

rece

ive

the

inte

rven

tions

.‡‡

‡‡(A

) Evi

den

ce is

from

end

-poi

nts

of w

ell-

des

igne

d R

CTs

tha

t p

rovi

de

a co

nsis

tent

pat

tern

of fi

ndin

gs in

the

pop

ulat

ion

for

whi

ch t

he r

ecom

men

dat

ion

is m

ade.

Cat

egor

y A

req

uire

s su

bst

antia

l num

ber

s of

stu

die

s in

volv

ing

sub

stan

tial n

umb

ers

of

par

ticip

ants

. (B

) Evi

den

ce is

from

end

-poi

nts

of in

terv

entio

n st

udie

s th

at in

clud

e on

ly a

lim

ited

num

ber

of p

atie

nts,

pos

thoc

or

sub

grou

p a

naly

sis

of R

CTs

or

met

a-an

alys

is o

f RC

Ts. I

n ge

nera

l, ca

tego

ry B

per

tain

s w

hen

few

ran

dom

ised

tria

ls e

xist

, the

y ar

e sm

all i

n si

ze, t

hey

wer

e un

der

take

n in

a p

opul

atio

n th

at d

iffer

s fr

om t

he t

arge

t p

opul

atio

n of

the

rec

omm

end

atio

n or

the

res

ults

are

som

ewha

t in

cons

iste

nt. (

C) E

vid

ence

is fr

om o

utco

mes

of u

ncon

trol

led

or

non-

rand

omis

ed t

rials

or

from

ob

serv

atio

nal

stud

ies.

(D) T

his

cate

gory

is u

sed

onl

y in

cas

es w

here

the

pro

visi

on o

f som

e gu

idan

ce w

as d

eem

ed v

alua

ble

but

the

clin

ical

lite

ratu

re a

dd

ress

ing

the

sub

ject

was

insu

ffici

ent

to ju

stify

pla

cem

ent

in o

ne o

f the

oth

er c

ateg

orie

s. T

he P

anel

con

sens

us is

bas

ed

on c

linic

al e

xper

ienc

e or

kno

wle

dge

tha

t d

oes

not

mee

t th

e cr

iteria

list

ed a

bov

e.§§

§§(A

) Hig

h, (B

) mod

erat

e, (C

) low

, (D

) ver

y lo

w.

¶¶

¶¶

Leve

l 1: W

e re

com

men

d. L

evel

2: W

e su

gges

t. N

o gr

ade:

Use

d, t

ypic

ally

, to

pro

vid

e gu

idan

ce b

ased

on

com

mon

sen

se o

r w

here

the

top

ic d

oes

not

allo

w a

deq

uate

ap

plic

atio

n of

evi

den

ce.

****

*(A

) Gui

del

ines

are

sup

por

ted

by

at le

ast

one

larg

e p

ublis

hed

RC

T or

mor

e. (B

) Gui

del

ines

are

sup

por

ted

by

larg

e op

en t

rials

or

smal

ler

tria

ls w

ith c

onse

nsus

res

ults

. (C

) Gui

del

ines

are

der

ived

from

sm

all o

r co

ntro

vers

ial s

tud

ies

or r

epre

sent

the

op

inio

n of

th

e gr

oup

of e

xper

ts.

††††

†I: E

vid

ence

from

at

leas

t on

e w

ell-

exec

uted

ran

dom

ised

, con

trol

led

tria

l. II:

Evi

den

ce fr

om a

t le

ast

one

wel

l-d

esig

ned

clin

ical

tria

l with

out

rand

omis

atio

n; c

ohor

t or

cas

e-co

ntro

lled

ana

lytic

stu

die

s (p

refe

rab

ly fr

om m

ore

than

one

cen

tre)

; mul

tiple

tim

e-se

ries

stud

ies

or d

ram

atic

res

ults

from

unc

ontr

olle

d e

xper

imen

ts. I

II: E

vid

ence

from

op

inio

ns o

f res

pec

ted

aut

horit

ies

bas

ed o

n cl

inic

al e

xper

ienc

e, d

escr

iptiv

e st

udie

s or

rep

orts

of e

xper

t co

mm

ittee

s.§§

§§§(

A) B

oth

stro

ng e

vid

ence

for

effic

acy

and

sub

stan

tial c

linic

al b

enefi

t su

pp

ort

reco

mm

end

atio

n fo

r us

e. S

houl

d a

lway

s b

e of

fere

d. (

B) M

oder

ate

evid

ence

for

effic

acy—

or s

tron

g ev

iden

ce fo

r ef

ficac

y, b

ut o

nly

limite

d c

linic

al b

enefi

t—su

pp

orts

re

com

men

dat

ion

for

use.

Sho

uld

gen

eral

ly b

e of

fere

d. (

C) E

vid

ence

for

effic

acy

is in

suffi

cien

t to

sup

por

t a

reco

mm

end

atio

n fo

r or

aga

inst

use

or

evid

ence

for

effic

acy

mig

ht n

ot o

utw

eigh

ad

vers

e co

nseq

uenc

es (e

g, d

rug

toxi

city

, dru

g in

tera

ctio

ns) o

r co

st

of t

he c

hem

opro

phy

laxi

s or

alte

rnat

ive

app

roac

hes.

Op

tiona

l. (D

) Mod

erat

e ev

iden

ce fo

r la

ck o

f effi

cacy

or

for

adve

rse

outc

ome

sup

por

ts a

rec

omm

end

atio

n ag

ains

t us

e. S

houl

d g

ener

ally

not

be

offe

red

. (E

) Goo

d e

vid

ence

for

lack

of e

ffica

cy o

r fo

r ad

vers

e ou

tcom

e su

pp

orts

a r

ecom

men

dat

ion

agai

nst

use.

Sho

uld

nev

er b

e of

fere

d.

‡‡‡‡

‡(I)

At

leas

t on

e p

rop

erly

ran

dom

ised

tria

l with

clin

ical

end

poi

nts.

(II)

Clin

ical

tria

ls e

ither

not

ran

dom

ised

or

cond

ucte

d in

oth

er p

opul

atio

ns. (

III) E

xper

t op

inio

n. ¶

¶¶

¶¶

(A) P

refe

rred

; sho

uld

gen

eral

ly b

e of

fere

d. (

B) A

ltern

ativ

e; a

ccep

tab

le t

o of

fer.

(C) O

ffer

whe

n p

refe

rred

or

alte

rnat

ive

regi

men

s ca

nnot

be

give

n. (D

) Sho

uld

gen

eral

ly n

ot b

e of

fere

d. (

E) S

houl

d n

ever

be

offe

red

. *

****

*I: E

vid

ence

from

at

leas

t on

e R

CT;

II: E

vid

ence

from

(1) a

t le

ast

one

wel

l-d

esig

ned

clin

ical

tria

l, w

ithou

t ra

ndom

isat

ion,

(2) c

ohor

t or

cas

e-co

ntro

lled

ana

lytic

stu

die

s, (3

) mul

tiple

tim

es s

erie

s, (4

) dra

mat

ic r

esul

ts fr

om u

ncon

trol

led

exp

erim

ents

III

evid

ence

from

op

inio

ns o

f res

pec

ted

aut

horit

ies

on t

he b

asis

of c

umul

ativ

e p

ublic

hea

lth e

xper

ienc

e, d

escr

iptiv

e st

udie

s or

rep

orts

of e

xper

t co

mm

ittee

s. †

††††

†A h

ighl

y re

com

men

ded

in a

ll ci

rcum

stan

ces,

II r

ecom

men

ded

; im

ple

men

tatio

n m

ight

be

dep

end

ent

on r

esou

rce

avai

lab

ility

, C m

ight

be

cons

ider

ed u

nder

exc

eptio

nal c

ircum

stan

ces.

‡‡‡

‡‡‡(

A) L

evel

1+

+ a

nd d

irect

ly a

pp

licab

le t

o th

e ta

rget

pop

ulat

ion

or le

vel 1

+ a

nd d

irect

ly a

pp

licab

le t

o th

e ta

rget

pop

ulat

ion

AN

D c

onsi

sten

cy o

f res

ults

. Evi

den

ce fr

om N

ICE

tec

hnol

ogy

app

rais

al. (

B) L

evel

2+

+, d

irect

ly a

pp

licab

le t

o th

e ta

rget

pop

ulat

ion

and

dem

onst

ratin

g ov

eral

l con

sist

ency

of r

esul

ts o

r ex

trap

olat

ed e

vid

ence

from

1+

+ o

r 1+

. (C

) Lev

el 2

+, d

irect

ly a

pp

licab

le t

o th

e ta

rget

pop

ulat

ion

and

dem

onst

ratin

g ov

eral

l con

sist

ency

of r

esul

ts o

r ex

trap

olat

ed e

vid

ence

from

2+

+. (

D) L

evel

3 o

r 4

or

extr

apol

ated

from

2+

or

form

al c

onse

nsus

or

extr

apol

ated

from

leve

l 2 c

linic

al e

vid

ence

sup

ple

men

ted

with

hea

lth e

cono

mic

mod

ellin

g. D

(GP

P):

A g

ood

pra

ctic

e p

oint

(GP

P) i

s a

reco

mm

end

atio

n b

ased

on

the

exp

erie

nce

of t

he G

DG

.A

RA

, Aus

tral

ian

Rhe

umat

olog

ical

Ass

ocia

tion;

BTS

, Brit

ish

Thor

acic

Soc

iety

; CD

C, c

entr

e fo

r d

isea

se c

ontr

ol; C

TC, C

anad

ian

Tub

ercu

losi

s C

omm

ittee

; EB

PG

, Eur

opea

n B

est

Pra

ctic

e G

uid

elin

e E

xper

t G

roup

on

Ren

al T

rans

pla

ntat

ion;

EC

DC

, Eur

opea

n C

entr

e fo

r D

isea

se P

reve

ntio

n an

d C

ontr

ol; G

RA

DE

, Gra

din

g of

Rec

omm

end

atio

ns A

sses

smen

t, D

evel

opm

ent

and

Eva

luat

ion;

KD

IGO

, Kid

ney

Dis

ease

Imp

rovi

ng G

lob

al O

utco

mes

; NC

CC

C, T

he N

atio

nal C

olla

bor

atin

g C

entr

e fo

r C

hron

ic C

ond

ition

s; N

ICE

, N

atio

nal I

nstit

ute

for

Hea

lth a

nd C

are

Exc

elle

nce;

NS

, not

sp

ecifi

ed; P

HE

X, P

hilip

pin

e G

uid

elin

es o

n P

erio

dic

Hea

lth E

xam

inat

ion;

RC

T, r

and

omis

ed c

ontr

ol s

tud

y; S

A, S

outh

Afr

ica;

SE

IMC

, Sp

anis

h S

ocie

ty o

f Inf

ectio

us D

isea

se a

nd C

linic

al M

icro

bio

logy

; S

EPA

R, S

pan

ish

Soc

iety

of R

esp

irato

ry D

isea

se a

nd T

hora

cic

Sur

gery

; SIG

N, S

cott

ish

Inte

rcol

legi

ate

Gui

del

ines

Net

wor

k; T

NF,

tum

our

necr

osis

fact

or.

Tab

le 1

C

ontin

ued



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stem cell transplantation33 and three for all forms of solid organ transplantation.3 35 37

Three guidelines addressed LTBI in patients with HIV.9 39 40 There were nine other guidelines which discussed screening in all at risk populations.10 41–48 Six of these also included discussion on patients with HIV41–45 47 and four were IGRA specific guidelines, although these guidelines also used TST as part of their screening strategies.41 43 44 46 Three guidelines were developed in countries with a high prevalence of TB (South Africa and Philippines).20 24 40

Across the guidelines, the methods for liter-ature review were not always specified. Liter-ature review was conducted in 32 guidelines (84%),1 3 9 10 15–22 24 26–35 37–39 41–46 48 of which 12 based their recommendations on a combination of the literature review and expert consensus.3 9 10 15–18 20 21 26 29 34 37 43–46 Two guidelines were based on expert consensus alone.23 42 Twenty guide-lines graded the level of evidence.3 9 10 17 18 24 27–30 32 34–39 42 46 48 Furthermore, 17 guidelines graded the strength of their recommendations.3 9 10 24 26 28–34 38 39 41 45 48 Where evidence was graded, it was often of low quality. Only nine (24%) guidelines were peer reviewed,9 10 17 19 20 24 29 30 48 with five (13%) made available for public consultation prior to publication.9 19 20 24 48 Only one guideline included a formal cost-effectiveness analysis48 which suggested that TST was more cost effective compared with the IGRA. The incre-mental cost-effectiveness ratio was influenced by prevalence of disease and age of the patients.

Methodological qualityTable 2 summarises the AGREE domain scores of each guideline. The mean AGREE score (and range) for all guidelines was 55% (0%–100%). In terms of scope and purpose, on average 80% (56%–100%) of criteria were met for all guidelines. The average score for stakeholder involve-ment was 51% (11%–97%), for rigour of development 47% (10%–93%), clarity and presentation 74% (50%–92%), applicability 47% (0%–92%) and editorial independence 35% (0%–92%). The overall domain mean score was 55% (35%–80%).

Weighted Kappa scores (κ) to assess inter-rater agree-ment ranged from a score between poor to very good, with the majority being moderate (0.41–0.60) to very good (0.81–1.00). The overall weighted score was 0.65 (95% CI 0.60–0.69), with good concordance between reviewers. The AGREE scores did not improve with later guidelines and over time.

textual synthesisA summary of the guidelines and the recommendations are provided in table 3. Most guidelines recommended screening in all immunosuppressed patients, and treatment if there was clinical evidence of LTBI.

screening for latent tb infectionPopulations of interestMost clinical practice guidelines recommended screening for LTBI in patients starting immunosuppression or were

highly likely to start immunosuppression, and patients immunosuppressed due to concurrent illness, including patients with HIV and/or undergoing solid organ and bone-marrow transplantation.3 15–20 22 24 26 33 35 37 39 47 48 Although medical immunosuppression was mostly biological therapy, two guidelines specified recommendations for patients who have received medical immunosuppression such as metho-trexate,17 32 cyclosporine and T cell blocking agents for the management of autoimmune disease.17 A third guideline which considered all immunosuppressed patients also spec-ified the use of non-biological therapies.47

screening modalities and frequenciesA combination of TST and/or IGRA testing, chest X-ray, detailed background history (including previous exposure to other individuals with TB) and risk factor assessment (travel or migration from endemic areas) was the most frequent recommendation for LTBI screening in immu-nosuppressed individuals.1 17 18 21 23 24 26 29–32 47 The recom-mended choice of screening modalities and their frequency were reliant on test availability and costs. The TST is widely available and economical.10

In guidelines pertaining to medical immunosuppres-sion, the recommendations for screening varied consid-erably between the use of TST and IGRA. Concurrent testing with both TST and IGRA was supported in six guidelines,16 18 20 22 26 32 however, three recommended the use of IGRA alone.15 28 30 Seven guidelines supported TST screening alone, but these recommendations were published prior to 2011.17 19 21 23 24 27 29 Two other guidelines recommended the use of either the TST or IGRA.1 22 In addition, two other guidelines recommended IGRA for BCG vaccinated individuals.16 17

In patients who require long-term maintenance medical immunosuppression, repeat testing at yearly intervals using IGRA was recommended by three guidelines,17 28 31 but two advocated against this, as the benefits of frequent IGRA screening was questionable.16 27 IGRA was recommended by one guideline in the presence of (any) skin disease due to difficulties in inoculating the TST in many of these cases.18

For transplant recipients, those with HIV and other immunosuppressed individuals, most guidelines acknowl-edged the added value of including TST and IGRA in the screening algorithm.9 10 33 35 37–39 41–46 48 Two guidelines specified the preference for IGRA over TST as the stan-dard triage screening tool for LTBI, because of the high false positive rates associated with TST,34 particularly among those who had been vaccinated with BCG.47 However, across all guidelines, among BCG vaccinated individ-uals, two guidelines recommended a two-step strategy for screening LTBI.31 42 TST was often considered as the triage test. If negative, IGRA was recommended as the second test to confirm the diagnosis. This has also been recommended to increase case detection in five other guidelines.17 20 30 35 46

Costs were also considered as a key factor in determining the frequency and modality of screening in immunosup-pressed individuals. The WHO have suggested IGRA and/or TST may be used in high-income and upper-middle-income



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Tab

le 2

G

rad

e of

rec

omm

end

atio

n

Gui

del

ine

nam

eS

cop

e an

d

pur

po

se (%

)S

take

hold

er

invo

lvem

ent

(%)

Rig

our

of

dev

elo

pm

ent

(%)

Cla

rity

and

p

rese

ntat

ion

(%)

Ap

plic

abili

ty (%

)E

dit

ori

al

ind

epen

den

ce (%

)W

eig

hted

Kap

pa

Sco

res

(Qua

dra

tic)

95%

CI

AR

A 2

0101

7531

1067

250

0.74

0.56

to

0.92

Agu

ado

et a

l 200

9372

2824

7229

580.

760.

62 t

o 0.

90

CD

C 2

0169

8989

8175

7783

0.29

−0.

14 t

o 0.

71

WH

O 2

01510

9794

8889

9288

0.67

0.27

to

1.00

Beg

linge

r et

al 2

00715

7542

2367

250

0.72

0.54

to

0.91

Can

tini e

t al

201

51689

5355

8956

380.

800.

63 t

o 0.

97

Doh

erty

et

al 2

00817

9244

7586

7158

0.55

0.19

to

0.91

Dua

rte

et a

l 201

21886

4431

8352

00.

670.

46 t

o 0.

89

Fons

eca

et a

l 200

81992

7273

8660

40.

740.

53 t

o 0.

95

Hod

kins

onet

al 2

01320

8383

5675

7125

0.00

−0.

27 t

o 0.

27

Kav

anag

het

al 2

00821

6433

2967

150

0.61

0.39

to

0.82

Kei

th e

t al

201

42283

4245

5019

420.

610.

27 t

o 0.

92

Koi

ke e

t al

200

72378

3328

5610

290.

410.

08 t

o 0.

75

Lich

auco

et

al 2

00624

8969

6778

650

0.64

0.27

to

1.00

Mir

Vila

dric

h e

t al

201

62681

4229

7540

420.

660.

44 t

o 0.

88

Mok

et

al 2

01127

6936

2853

2733

0.53

0.24

to

0.82

Nor

dga

ard

-Las

sen

et a

l 20

1228

7839

4864

350

0.75

0.60

to

0.90

Sal

mon

200

22572

4213

640

00.

760.

55 t

o 0.

97

BTS

200

52992

6991

8971

630.

32−

0.05

to

0.70

Sm

ith e

t al

200

93094

6180

8365

750.

770.

51 t

o 1.

00

Sol

ovic

et

al 2

01031

6933

3581

4438

0.66

0.41

to

0.92

Car

rasc

osa

et a

l 201

63267

4246

6121

830.

710.

56 t

o 0.

87

Bum

bac

ea e

t al

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countries.10 Given the anticipated costs of IGRA, and the general acceptance of TST by clinicians and patients, TST was preferred in low income countries, despite the lower test accuracies of TST.10 In the high prevalence settings of South Africa and the Philippines, there was no reliable testing method: a combined TST and IGRA approach was recommended in one guideline,20 treatment of all patients with HIV without screening was recommended in another40 and TST alone in one guideline.24

Defining screen positive and negative resultsCriteria for TST positivity varied across guidelines. Some recommended a TST-induced reaction of at least 5 mm diameter in all populations, to allow for the treatment of patients in high-risk settings.17 19–21 26 35–37 40 48 Other recom-mendations for the threshold diameter ranged from 6 mm to 20 mm.18–21 23 24 26 27 31 33 Where the TST result was initially negative, two guidelines recommended repeat testing.23 45 In all guidelines, an individual was deemed to be at risk for LTBI if either the TST or IGRA was positive.

Are these recommendations valid?There is a body of evidence assessing the test performance characteristics of TST and IGRA in the general population. However, these recommendations were sourced largely from observational studies performed in middle to high-in-come countries and did not include immunosuppressed patients from low-resource settings and with low certainty of the evidence. Given the low test sensitivity of TST in immunosuppressed patients, some guidelines suggested a two-stage screening, first using TST and then IGRA to increase the detection rates of LTBI.17 20 30 35 46 Among those who are immunosuppressed and had previously been vaccinated with BCG, IGRA generally performs better than TST. IGRA test sensitivity and specificity varies between 67%–75% and 93%–99%, respectively.33 43 However, given the concerns of spectrum bias, most guidelines suggested caution in the interpretation of test results among immu-nosuppressed hosts.

treatment for latent tb infectionPopulation of interestsEither a positive TST or IGRA was considered suffi-cient evidence to warrant further evaluation. Prior to LTBI treatment, exclusion of active TB was recom-mended.1 9 15 17 18 25 26 29 30 32 35 42–44 47 48 Once active TB was excluded, LTBI treatment was recommended. Treatment for LTBI was also indicated for those who were BCG vaccinated, because BCG status may indi-cate time spent in an area with a high prevalence of LTBI.34 Furthermore, in South Africa, where there is a high prevalence of TB, treatment for LTBI was recom-mended in all patients after exclusion of active TB in the setting of HIV.40 Also, most clinical practice guide-lines recommended LTBI treatment where clinical suspicion was high, regardless of the IGRA and TST test findings.1 3 15 19 20 24 26 28 29 33 35–38G

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Table 3 Summary of recommendations

Guidelines Population

Screening process Treatment

methodTreatment duration

Timing before immunosuppressionHistory TST IGRA CXR

ARA 20101 Biological therapy X X X Isoniazid* 6–9 months 1–2 months

Aguado et al 20093 Transplant recipients X X X Isoniazid 9 months Before transplant

CDC 20169 Patients with HIV X X Isoniazid 9 months NS

WHO 201510 Low-middle income countries

X X Isoniazid 6 months NS

Beglinger et al 200715

Biological therapy X X X Isoniazid OR rifampicin

NS 1 month

Cantini et al 201516 Biological therapy X X X Isoniazid 9 months 1 month

Doherty 200817 Patients with psoriasis X X X Isoniazid 9 months 1–2 months or longer

Duarte et al 201218 Biological therapy X X X Isoniazid 9 months 1–2 months

Fonseca et al 200819 Biological therapy X X X Isoniazid 6–9 months 1 month

Hodkinson et al 201320

Patients with rheumatoid arthritis

X X X X Isoniazid 9 months 1 month

Kavanagh et al 200821

Biological therapy X X X Isoniazid 9 months Pre-immunosuppression

Keith et al 201422 Bullous dermatosis X X NS NS NS

Koike et al 200723 Biological therapy X X X Isoniazid NS NS

Lichauco et al 200624

Biological therapy X X Isoniazid 9 months 1 month

Salmon200225 Biological therapy X X Rifampicin and pyrazinamide

2 months 3 weeks

Mir Viladrich et al 201626

Biological therapy X X X Isoniazid 9 months 4 weeks

Mok et al 201127 Biological therapy X Isoniazid 9 months 4 weeks

Nordgaard-Lassen et al 2012 28

Biological therapy X Isoniazid 9 months 4 weeks

BTS 200529 Biological therapy X X X Isoniazid 6 months Concurrent

Smith et al 200930 Biological therapy X X Isoniazid OR Isoniazid and rifampicin

6 months OR 3 months

2 months

Solovic et al 201031 Biological therapy X X X X Isoniazid 9 months 4 weeks

Carrasoca et al 201632

Methotrexate therapy X X X Isoniazid NS NS

Bumbacea et al 201233

Transplant recipients X X NS NS Before transplant

KDIGO 200934 Renal transplant X X Isoniazid 9 months NS

Meije et al 201435 Transplant recipients X X Isoniazid 9 months NS

EBPG 200236 Renal transplant recipients

X X X Isoniazid 9 months NS

Subramanian 201337 Transplant recipients X X X X Isoniazid 9 months Before or after transplant

Tomblyn et al 200938 SCT recipients X X X Isoniazid 9 months NS

Pozniak et al 201139 Patients with HIV X X Isoniazid 6 months NS

SA 201040 Patients with HIV X Isoniazid 6 months NS

Santin et al 201741 Patients with HIV X X X NS NS NS

Biological therapy X X X NS NS NS

Transplant recipients X X X NS NS NS

Continued



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Intervention and durationRecommendations for the treatment of LTBI were largely similar across guidelines, regardless of the mode of immunosuppression. In most guidelines, isoniazid 300 mg daily with pyridoxine was recommended for a duration of 9 months.3 9 16–21 24–27 29 31 33–39 42 Six months of isoniazid therapy was considered less efficacious,18 but was recommended in one guideline.48 Three guidelines suggested a flexible treatment regimen of 6–9 months of the combined therapies.19 30 47 Four guidelines did not specify duration.15 23 32 45

Rifamycin-based therapy (10 mg/kg/day) either alone or for three10 or four1 3 9 10 15–18 24 26 27 31 33 35–39 42 months was the second most frequently reported treatment strategy among patients who tested positive for LTBI. This was thought to be useful when isoniazid was contraindicated or not tolerated,27 with one guideline describing the option as cheaper, but with more drug-drug interactions.18 Rifampicin plus isoniazid for three1 10 15–19 25 26 29–31 39 or 4 months10 24 was also an option. Rifampicin plus isoni-azid for 3 months was stipulated as a primary alternative therapy to isoniazid in two guidelines.30 48 Other options included rifabutin for 4 months9 42 or 3 months of weekly rifapentine and isoniazid.9 10 Finally, rifampicin and pyra-zinamide for a shorter 2-month regimen was considered as an option in eight guidelines,3 25 29 35–39 with most being in the transplantation setting. The shorter duration of treatment was considered advantageous for those main-tained on the transplant waiting list.3 35–38 However, a biological therapy-based guideline advised against this option due to the increased risk of hepatotoxicity.24

In the transplantation and HIV settings, some guide-lines specified avoidance of rifamycins, given the poten-tial drug-drug interactions with calcineurin inhibitors and protease inhibitors.3 35 37 However, therapeutic drug monitoring may mitigate against the potential for such interactions.34 Several other non-rifamycin based alterna-tives were recommended and included ethambutol with levofloxacin or moxifloxacin for 6 months,3 3712 weeks of rifapentine and isoniazid and 6 months of isoniazid with ethambutol.24

Close monitoring with monthly liver function tests and for peripheral neuropathy was recommended while on treatment for all patients.3 9 10 17 18 26 31 35 37 40 47 Coad-ministration of vitamin B6 (pyridoxine) was suggested universally, to reduce the risk of peripheral neuropathy associated with isoniazid. If there were treatment inter-ruptions for more than 2 months, one guideline recom-mended clinical and radiological reassessment for TB.42

timing of preventive therapyIn patients who are medically immunosuppressed, most guidelines recommended delaying medical therapy for 1 month after commencement of LTBI treatment where possible, to reduce the risk of TB reactivation.15–18 20 24–28 Alternative waiting periods varied between 3 weeks25 47 to 2 months.30 One guideline preferred a prolonged delay, but did not provide a time frame.21 However, if the under-lying disease was severe, earlier institution of immuno-suppressive agents was accepted17 29 once active TB was excluded.28

Guidelines Population

Screening process Treatment

methodTreatment duration

Timing before immunosuppressionHistory TST IGRA CXR

Al Jahdali et al 201042

Susceptible populations

X X Isoniazid 9 months NS

ECDC 201143 Immunocompromised X X NS NS NS

Mazurek et al 201044 Susceptible populations

X X X X NS NS NS

Taylor et al (CDC 2005)45


X X X Isoniazid NS NS

CTC 200846 Immunocompromised X X NS NS NS

Japanese Society for Tuberculosis 201447


X X X Isoniazid 6–9 months 3 weeks before immunosuppressionNS for transplant

NICE 201648 Susceptible populations

X X X Isoniazid OR Isoniazid and rifampicin

6 months OR 3 months

NS

*Where isoniazid is used, it is always provided concurrently with pyridoxine prophylaxis.ARA, Australian Rheumatological Association; BTS, British Thoracic Society; CDC, centre for disease control; CTC, Canadian Tuberculosis Committee; CXR, chest X-ray; EBPG, European Best Practice Guideline Expert Group on Renal Transplantation; ECDC, European Centre for Disease Prevention and Control; IGRA, interferon gamma release assay; KDIGO, Kidney Disease Improving Global Outcomes; NICE, National Institute for Health and Care Excellence; NS, not specified; SA, South Africa; SCT, Stem cell transplant, TST, tuberculin skin test.

Table 3 Continued



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In transplant setting, patients with LTBI are recom-mended to commence treatment on the waiting list where possible, with treatment ideally completed prior to transplantation.3 33 35 37 38 However, treatment inter-ruption peritransplantation, with recommencement and completion of the treatment course once patients were clinically stable, may also be considered.33 35 37 LTBI treatment should not delay transplantation.38 In the setting of liver transplantation, the use of anti-TB medications has been associated with increased risk of hepatotoxicity. Thus, it was generally recommended that LTBI therapy be commenced after transplanta-tion, to avoid drug-related fulminant hepatitis while waiting for a donor organ.3 35 37

In patients with HIV, the timing of commencement of antiretroviral therapy in relation to LTBI treat-ment was not specified by clinical practice guidelines. Unlike treatment for active TB, immune reconstitu-tion related to LTBI treatment has not been docu-mented.9 Generally, it was recommended to initiate or continue antiretroviral treatment concurrently with treatment for LTBI.39 40

Are these recommendations valid?Overall, clinical practice guidelines recommended the use of isoniazid-based or rifamycin-based regimes for the treatment of LTBI. The evidence for recommen-dations was largely sourced from observational studies in high-income countries, thus limiting the ability to generalise recommendations to low-income countries. There was very little evidence about the exact time frame of delay before initiating treatment. In addition, side effects associated with the treatment of LTBI, such as hepatotoxicity, neuropathy, gastrointestinal toxicity and rash, were discussed in only 50% of the guide-lines.1 3 9 10 18 19 21 24 29 31 33 35–37 39 40 42 47 48

DIsCussIOnClinical practice guidelines for screening and treatment of LTBI vary in scope and their recommendations for screening modalities, frequency of screening and the target populations of interest. The two-stage screening approach of TST and IGRA was most frequently recommended because of improved test performance characteristics in high risk, immunosuppressed populations. Guidelines did not specify how to interpret a mismatch in results between TST and IGRA, but recommended treatment where either test was positive. For treatment, most recommendations suggested the use of isoniazid-based therapies for LTBI, but there were discrepancies in the duration and timing of commencing treatment. Nine months of isoniazid-based therapy appeared to be the preferred therapy for LTBI, and most agreed that treatment of LTBI should be initiated prior to commencement of immunosuppressive therapies.

While most guidelines conducted a comprehensive literature review, the evidence base supporting the recom-mendations was limited to observational studies without

trial-based evidence to support routine screening and treat-ment for LTBI in immunosuppressed patients. The rigour of guideline development lacks robustness. Less than half of the guidelines provided grading of the evidence and recommendations. Details regarding the methods used for formulating the recommendations were not adequately described, lacking transparency in the methodology and did not consistently link the recommendations to the corre-sponding level of evidence, both for screening and treat-ment of LTBI and the benefit-harm-cost relationship.

In this review, we found that public and stakeholder consultation was rarely reported in the development of the guidelines. Only 22% underwent a peer review process and 11% underwent public consultation. Engaging experts may improve guidelines by allowing criticism and suggestions.19 Expert clinicians were consulted in guideline development and included clinicians such as rheumatologists, gastro-enterologists, dermatologists, thoracic physicians, infec-tious diseases physicians and clinicians involved in treating patients with HIV. Public consultations and patient partici-pation can also improve guideline applicability.49 Although four guidelines used public consultation, none elaborated on how they have contributed to guideline development. Guideline applicability may be improved by active consumer involvement and engagement in the development, design and implementation process.

Inconsistencies exist in the recommendations for screening modalities and frequencies for LTBI. The TST evokes delayed hypersensitivity after intradermal application of a purified protein derivative.33 TST generally performs poorly in immunosuppressed patients, with reported esti-mates of 89% and 71% for test sensitivity and specificity, respectively.43 The lower test specificity may be due to the cross-reactivity with prior BCG vaccination15 34 and infec-tions with non-TB mycobacteria. Testing with IGRA iden-tifies adaptive immune response to TB-specific antigens which are not present in BCG strains, enabling greater specificity.42 43 Test sensitivity of TST and IGRA is uncer-tain or may be reduced among immunosuppressed hosts because of anergy.33 Determining the diagnostic accuracy of the IGRA and TST is complicated because of the absence of an accurate and valid reference standard. For example, underestimation of the true test sensitivity and specificity of the new test may occur if the imperfect reference incor-rectly classifies those with disease as no disease (false nega-tive) and those without disease as disease (false positive).

Multiple diagnostic algorithms for LTBI have been proposed to overcome the shortcomings of IGRA and TST, including the use of predefined multiple imperfect diag-nostic tests and clinical data to inform the prevalence esti-mates of LTBI in different settings. Despite this, prevalence of LTBI varies substantially, even in high-risk patients.50 Statistical methods such as latent class and Bayesian mixture analyses may overcome this limitation.51 52

Most guidelines recommended treatment for LTBI, including those who were screened negative but of high clinical risk. While this is of relevance and importance to at-risk immunosuppressed patients, interventions such



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as isoniazid and alternatives including rifampicin are not without adverse complications. No guidelines specified contraindications to treatment, except in the case of liver transplantation, where treatment was recommended to be delayed until after transplantation due to the increased risk of hepatotoxicity.3 35 37 Treatment of LTBI also has other potential drug toxicities, including neuropathy and drug-drug interactions, particularly for rifampicin-based regimens. Although many guidelines acknowledged these toxicities, the impact of overtreatment and the potential risk of adverse drug reactions were not quantified. Only two guidelines specified the growing concern of increasing rates of multidrug-resistant TB secondary to excess expo-sure to drug therapy.23 47 Furthermore, barriers to screening and treatment are only considered in one guideline, which stated that there were no barriers in a public hospital.41 This therefore would not apply in under-resourced settings or where public healthcare is not available.

In our systematic review, we used a reliable and vali-dated method using the AGREE II to assess guidelines for the screening for and treatment of LTBI. There was good agreement between the two reviewers. We have summarised the variability in the literature pertaining to LTBI, allowing for a consolidated approach to recommen-dations for screening and management of LTBI. However, limitations of our review are that we have only included guidelines written in the English language. Therefore, applicability of our findings to other settings, particularly those in low-income countries are uncertain. Future guide-lines should consider the specific health issues that are applicable to the population of interest, such as in low-in-come settings, and consider cost implications and barriers to screening and treatment. Very few guidelines discussed non-TNF based immunosuppression. This included two well-established medications—methotrexate and cyclo-phosphamide—for the management of autoimmune disease as well as newer biological treatments.17 Only one guideline included newer monoclonal agents30 and one for patients on regular methotrexate therapy.32 One of the key challenges for guideline developers is the translation and dissemination of these recommendations in clinical practice, which may transform care and improve health of the target population. Currently, there are limited training initiatives in the implementation of these guidelines in different cultural and resource settings. Future research, through direct engagement with local stakeholders, clini-cians and patients should therefore assess the features and processes that underpin success in research translation and adapt these strategies in practice.

Overall, the current clinical guidelines reaffirm the importance of LTBI screening and treatment. Although there are some discrepancies in terms of screening modali-ties, recommendation for the treatment of LTBI was consis-tent across all guidelines. Quality of evidence and rigour of guideline development varied. Therefore, there is a need to undertake better-quality studies, with international, multi-disciplinary and stakeholder involvement to consolidate current evidence. This is critical to support evidence-based

guidelines development and patient-centred practice to improve patient outcomes.

Author affiliations1Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, Australia2Centre for Transplant and Renal Research, Westmead Hospital, Westmead, New South Wales, Australia3School of Medicine, The University of Sydney, Sydney, New South Wales, Australia4Centre for Kidney Research, The Children’s Hospital, Westmead, New South Wales, Australia5Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia

Contributors TH: database search, selection of guidelines; grading of guidelines, assessing quality, interpretation; preparation of manuscript and editing. EA: selection of guidelines; grading of guidelines, assessing quality, interpretation; preparation of manuscript and editing. SC, AT, GW: preparation of manuscript and editing.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests SC reports grants from MSD Australia, outside the submitted work.

Patient consent Not required.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement Data are available on request.

Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.

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